Quinazolinones as PARP14 inhibitors

ABSTRACT

The present invention relates to quinazolinones and related compounds which are inhibitors of PARP14 and are useful, for example, in the treatment of cancer and inflammatory diseases.

FIELD OF THE INVENTION

The present invention relates to quinazolinones and related compoundswhich are inhibitors of PARP14 and are useful in the treatment ofcancer.

BACKGROUND OF THE INVENTION

Poly(ADP-ribose) polymerases (PARPs) are members of a family ofseventeen enzymes that regulate fundamental cellular processes includinggene expression, protein degradation, and multiple cellular stressresponses (Vyas S, et al. Nat Rev Cancer. 2014 Jun. 5; 14(7):502-509).The ability of cancer cells to survive under stress is a fundamentalcancer mechanism and an emerging approach for novel therapeutics. Onemember of the PARP family, PARP1, has already been shown to be aneffective cancer target in connection to cellular stress induced by DNAdamage, either induced by genetic mutation or with cytotoxicchemotherapy, with three approved drugs in the clinic and several othersin late stage development (Ohmoto A, et al. OncoTargets and Therapy.2017; Volume 10:5195).

The seventeen members of the PARP family were identified in the humangenome based on the homology within their catalytic domains (Vyas S, etal. Nat Commun. 2013 Aug. 7; 4:2240). However, their catalyticactivities fall into 3 different categories. The majority of PARP familymembers catalyze the transfer of mono-ADP-ribose units onto theirsubstrates (monoPARPs), while others (PARP1, PARP2, TNKS, TNKS2)catalyze the transfer of poly-ADP-ribose units onto substrates(polyPARPs). Finally, PARP13 is thus far the only PARP for whichcatalytic activity could not be demonstrated either in vitro or in vivo.PARP14 is a cytosolic as well as nuclear monoPARP. It was originallyidentified as BAL2 (B Aggressive Lymphoma 2), a gene associated withinferior outcome of diffuse large B cell lymphoma (DLBCL), together withtwo other monoPARPs (PARP9 or BAL1 and PARP15 or BAL3) (Aguiar R C, etal. Blood. 2000 Dec. 9; 96(13):4328-4334 and Juszczynski P, et al. MolCell Biol. 2006 Jul. 1; 26(14):5348-5359). PARP14, PARP9 and PARP15 arealso referred to as macro-PARPs due to the presence of macro-domains intheir N-terminus. The genes for the three macroPARPs are located in thesame genomic locus suggesting co-regulation. Indeed, the gene expressionof PARP14 and PARP9 is highly correlated across normal tissues andcancer types. PARP14 is overexpressed in tumors compared to normaltissues, including established cancer cell lines in comparison to theirnormal counterparts. Literature examples of cancers with high PARP14expression are DLBCL (Aguiar RCT, et al. J Biol Chem. 2005 Aug. 1;280(40):33756-33765), multiple myeloma (MM) (Barbarulo A, et al.Oncogene. 2012 Oct. 8; 32(36):4231-4242) and hepatocellular carcinoma(HCC) (Iansante V, et al. Nat Commun. 2015 Aug. 10; 6:7882). In MM andHCC cell lines RNA interference (RNAi) mediated PARP14 knockdowninhibits cell proliferation and survival. Other studies show that theenzymatic activity of PARP14 is required for survival of prostate cancercell lines in vitro (Bachmann S B, et al. Mol Cancer. 2014 May 27;13:125).

PARP14 has been identified as a downstream regulator of IFN-γ and IL-4signaling, influencing transcription downstream of STAT1 (in the case ofIFN-γ) (Iwata H, et al. Nat Commun. 2016 Oct. 31; 7:12849) or STAT6 (inthe case of IL-4) (Goenka S, et al. Proc Natl Acad Sci USA. 2006 Mar. 6;103(11):4210-4215; Goenka S, et al. J Biol Chem. 2007 May 3;282(26):18732-18739; and Mehrotra P, et al. J Biol Chem. 2010 Nov. 16;286(3):1767-1776). Parp14−/− knockout (KO) mice have reduced marginalzone B cells, and the ability of IL-4 to confer B cell survival in vitrowas reduced as well in the Parp14 KO setting (Cho S H, et al. Blood.2009 Jan. 15; 113(11):2416-2425). This decreased survival signaling waslinked mechanistically to decreased abilities of Parp14 KO B cells tosustain metabolic fitness and to increased Mcl-1 expression. Parp14 KOcan extend survival in the E t-Myc lymphoma model, suggesting a role ofPARP14 in Myc-driven lymphomagenesis (Cho S H, et al. Proc Natl Acad SciUSA. 2011 Sep. 12; 108(38):15972-15977). Gene expression data pointtowards roles of PARP14 in human B cell lymphoma as well. The BALproteins, including PARP14, are highly expressed in host response (HR)DLBCLs, a genomically defined B cell lymphoma subtype characterized witha brisk inflammatory infiltrate of T and dendritic cells and presence ofan IFN-γ gene signature (Molecular profiling of diffuse large B-celllymphoma identifies robust subtypes including one characterized by hostinflammatory response. Monti S, et al. Blood. 2005; 105(5):1851).Indeed, PARP14 is believed to be an interferon stimulated gene with itsmRNA increased by stimulation of various cell systems with all types ofinterferon (I, II and III; www.interferome.org).

Due to its role downstream of IL-4 and IFN-γ signaling pathways PARP14has been implicated in T helper cell and macrophage differentiation.Genetic PARP14 inactivation in macrophages skews to a pro-inflammatoryM1 phenotype associated with antitumor immunity while reducing apro-tumor M2 phenotype. M1 gene expression, downstream of IFN-γ, wasfound to be increased while M2 gene expression, downstream of IL-4, wasdecreased with PARP14 knockout or knockdown in human and mousemacrophage models. Similarly, genetic PARP14 knockout has been shown toreduce a Th2 T helper cell phenotype in the setting of skin and airwayinflammation, again pertaining to the regulatory role of PARP14 in IL-4signal transduction (Mehrotra P, et al. J Allergy Clin Immunol. 2012Jul. 25; 131(2):521 and Krishnamurthy P, et al. Immunology. 2017 Jul.27; 152(3):451-461).

PARP14 was shown to regulate the transcription of STAT6 (activator oftranscription 6) and promotes T_(H)2 responses in T cells and B cells,which are known to promote allergic airway disease (asthmaticcondition). Genetic depletion of PARP14 and its enzymatic activity in amodel of allergic airway disease led to reduced lung inflammation andIgE levels, which are key readouts of the asthmatic process in thismodel. In addition, the enzymatic activity of PARP14 promoted a T_(H)2phenotype differentiation in a STAT6 dependent manner. (Mehrotra P, etal. J Allergy Clin Immunol. 2012 Jul. 25; 131(2):521) Therefore,inhibition of the PARP14 catalytic activity may be a potential noveltherapy for allergic airway disease.

There is an ongoing need for new medications that can treat diseasessuch as certain cancers and inflammatory conditions characterized byabnormal expression or activity of PARP14. The compounds, compositions,and methods described herein help meet these and other needs.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein constituentmembers are defined below.

The present invention is further directed to a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.

The present invention is further directed to a method of inhibiting theactivity of PARP14 comprising contacting a compound of Formula I, or apharmaceutically acceptable salt thereof, with PARP14.

The present invention is further directed to a method of decreasingIL-10 in a cell comprising contacting a compound of Formula I, or apharmaceutically acceptable salt thereof, with the cell.

The present invention is further directed to a method of treating adisease or disorder in a patient in need of treatment, where the diseaseor disorder is characterized by overexpression or increased activity ofPARP14, comprising administering to the patient a therapeuticallyeffective amount of a compound Formula I, or a pharmaceuticallyacceptable salt thereof.

The present invention is further directed to a method of treating cancerin a patient in need of treatment comprising administering to thepatient a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

The present invention is further directed to a method of treating aninflammatory disease in a patient in need of treatment comprisingadministering to the patient a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the mRNA expression levels of PARP14 in variouscancer types, compared to their matched normal tissue.

FIGS. 2A and 2B illustrate that in vitro treatment with various PARP14inhibitors decreases IL-10 production in IL-4 stimulated M2-likemacrophages.

FIG. 3A illustrates that a PARP14 inhibitor reduces tumor growth in a4T1 murine syngeneic model. FIG. 3B shows the plasma concentration ofthe PARP14 inhibitor following the last dose at the study endpoint.

FIG. 4A illustrates that a PARP14 inhibitor reduces tumor growth in aLL/2 murine syngeneic model. FIG. 4B shows the survival benefit ofadministration of the PARP14 inhibitor in the LL/2 syngeneic model. FIG.4C shows the plasma concentration of the PARP14 inhibitor following thelast dose at the study endpoint.

DETAILED DESCRIPTION

The present invention is directed to a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

W is CR^(W) or N;

X is CR^(X) or N;

Y is CR^(Y) or N;

Z is CR^(Z) or N;

wherein no more than two of W, X, Y, and Z are simultaneously N;

Ring A is monocyclic or polycyclic C₃₋₁₄ cycloalkyl or Ring A ismonocyclic or polycyclic 4-18 membered heterocycloalkyl, wherein Ring Ais optionally substituted by 1, 2, 3, or 4 R^(A), and Ring A is attachedto the -(L)_(m)- moiety of Formula I through a non-aromatic ring whenRing A is polycyclic;

L is —(CR⁵R⁶)_(t)—, —(CR⁵R⁶)_(p)—O—(CR⁵R⁶)_(q)—,—(CR⁵R⁶)_(p)—S—(CR⁵R⁶)_(q)—, —(CR⁵R⁶)_(p)—NR³—(CR⁵R⁶)_(q)—,—(CR⁵R⁶)_(p)—CO—(CR⁵R⁶)_(q)—, —(CR⁵R⁶)_(r)—C(O)O—(CR⁵R⁶)_(s)—,—(CR⁵R⁶)_(r)—CONR³—(CR⁵R⁶)_(s)—, —(CR⁵R⁶)_(p)—SO—(CR⁵R⁶)_(q)—,—(CR⁵R⁶)_(p)—SO₂—(CR⁵R⁶)_(q)—, —(CR⁵R⁶)_(r)—SONR³—(CR⁵R⁶)_(s)—, or—NR³CONR⁴—;

R¹ and R² are each, independently, selected from H and methyl;

R³ and R⁴ are each, independently, selected from H and C₁₋₄ alkyl;

R⁵ and R⁶ are each, independently, selected from H, halo, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, amino, C₁₋₄ alkylamino, and C₂₋₈dialkylamino;

each R^(A) is independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl of R^(A) are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from Cy¹,Cy¹—C₁₋₄ alkyl, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a1)SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1) NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1) NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R^(W), R^(X), R^(Y), and R^(Z) are each, independently, selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2)NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2) NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃-7cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10membered heterocycloalkyl-C₁₋₄ alkyl of R^(W), R^(X), R^(Y), or R^(Z)are each optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from Cy², Cy²—C₁₋₄ alkyl, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2)NR^(c2)C(═NR^(e2))NR^(c2)R^(d2) NR^(c2)R^(d2) NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

wherein when W is CR^(W), X is CR^(X), Y is CR^(Y), and Z is CR^(Z),then at least one of R^(W), R^(X), R^(Y), and R^(Z) is other than H;

each Cy¹ is independently selected from C₆₋₁₀ aryl, C₃₋₇ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, eachoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10membered heteroaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

each Cy² is independently selected from C₆₋₁₀ aryl, C₃₋₇ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, eachoptionally substituted by 1, 2, 3, or 4 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10membered heteroaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2) NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2) NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2) S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

each R^(a1), R^(b1), R^(e1), R^(d1), R^(a2), R^(b2), R^(c2), and R^(d2)is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10membered heterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10membered heterocycloalkyl-C₁₋₄ alkyl of R^(a1), R^(b1), R¹¹, R^(d1),R^(a2), R^(b2), R^(c2), or R^(d2) is optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from Cy³, Cy³—C₁₋₄ alkyl,halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3) NR^(c3)C(O)OR^(a3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), and S(O)₂NR^(c3)R^(d3);

each Cy³ is C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, or4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3,or 4 substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, OR^(a3),SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)NR^(c3)R^(d3) NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3) S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3);

R^(a3), R^(b3), R^(c3), and R^(d3) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, and 4-10 membered heterocycloalkyl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1, 2,or 3 substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

or R^(c1) and R^(d1) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3) NR^(c3)C(O)OR^(a3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3) and S(O)₂NR^(c3)R^(d3);

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3)OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3) NR^(c3)C(O)OR^(a3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), and S(O)₂NR^(c3)R^(d3);

each R^(e1), R^(e2), and R^(e3) is independently selected from H, C₁₋₄alkyl, and CN;

m is 0 or 1,

n is, 1, or 2;

p is 0, 1, or 2;

q is 0, 1, or 2, wherein p+q is 0, 1, or 2;

r is 0 or 1;

s is 0 or 1, where r+s is 0 or 1; and

t is 1, 2, or 3;

wherein any aforementioned heteroaryl or heterocycloalkyl groupcomprises 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom O, N, and S;

wherein one or more ring-forming C or N atoms of any aforementionedheterocycloalkyl group is optionally substituted by an oxo (═O) group;

wherein one or more ring-forming S atoms of any aforementionedheterocycloalkyl group is optionally substituted by one or two oxo (═O)groups;

wherein when W is CR^(W), X is CR^(X), Y is CR^(Y), and Z is CR^(Z) andwhen m is 1 or 2, then R^(X) and R^(Y) are not both methoxy;

wherein the compound is other than:

In some embodiments, W is CR^(W); X is CR^(X); Y is CR^(Y); and Z isCR^(Z).

In some embodiments, W is N; X is CR^(X); Y is CR^(Y); and Z is CR^(Z).

In some embodiments, W is CR^(W); X is N; Y is CR^(Y); and Z is CR^(Z).

In some embodiments, W is CR^(W); X is CR^(X); Y is N; and Z is CR^(Z).

In some embodiments, W is CR^(W); X is CR^(X); Y is CR^(Y); and Z is N.

In some embodiments, Ring A is monocyclic or polycyclic C₃₋₁₄ cycloalkyloptionally substituted by 1, 2, 3, or 4 R^(A), wherein Ring A isattached to the -(L)_(m)- moiety of Formula I through a non-aromaticring when Ring A is polycyclic.

In some embodiments, Ring A is monocyclic C₃₋₇ cycloalkyl optionallysubstituted by 1, 2, 3, or 4 R^(A).

In some embodiments, Ring A is cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl optionally substituted by 1, 2, 3, or 4 R^(A).

In some embodiments, Ring A is cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl.

In some embodiments, Ring A is cyclohexyl or cycloheptyl optionallysubstituted by 1, 2, 3, or 4 R^(A).

In some embodiments, Ring A is cyclohexyl or cycloheptyl.

In some embodiments, Ring A is cyclohexyl optionally substituted by 1,2, 3, or 4 R^(A).

In some embodiments, Ring A is cyclohexyl.

In some embodiments, Ring A is monocyclic or polycyclic 4-18 memberedheterocycloalkyl optionally substituted by 1, 2, 3, or 4 R^(A), andwherein Ring A is attached to the -(L)_(m)- moiety of Formula I througha non-aromatic ring when Ring A is polycyclic.

In some embodiments, Ring A is monocyclic 4-7 membered heterocycloalkyloptionally substituted by 1, 2, 3, or 4 R^(A).

In some embodiments, Ring A is monocyclic 4-7 membered heterocycloalkyl.

In some embodiments, Ring A is oxetanyl, tetrahydropyranyl, oxepanyl,azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl, optionallysubstituted by 1, 2, 3, or 4 R^(A).

In some embodiments, Ring A is oxetanyl, tetrahydropyranyl, oxepanyl,azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl.

In some embodiments, Ring A is oxetanyl, tetrahydropyranyl, oxepanyl,azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, ortetrahydrothiopyranyl optionally substituted by 1, 2, 3, or 4R^(A).

In some embodiments, Ring A is oxetanyl, tetrahydropyranyl, oxepanyl,azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, ortetrahydrothiopyranyl.

In some embodiments, Ring A is piperidinyl optionally substituted by 1,2, 3, or 4 R^(A).

In some embodiments, Ring A is piperidinyl.

In some embodiments, Ring A is piperidin-4-yl optionally substituted by1, 2, 3, or 4 R^(A).

In some embodiments, Ring A is piperidin-4-yl.

In some embodiments, Ring A is tetrahydropyranyl optionally substitutedby 1, 2, 3, or 4 R^(A).

In some embodiments, Ring A is tetrahydropyranyl.

In some embodiments, Ring A is tetrahydropyran-4-yl optionallysubstituted by 1, 2, 3, or 4 R^(A).

In some embodiments, Ring A is tetrahydropyran-4-yl.

In some embodiments, L is —(CR⁵R⁶)_(t)—.

In some embodiments, L is —(CR⁵R⁶)_(t)— and t is 1.

In some embodiments, L is —(CR⁵R⁶)_(t)— and t is 2.

In some embodiments, L is —(CR⁵R⁶)_(t)— and t is 3.

In some embodiments, L is —CH₂—.

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, R¹ and R² are both H.

In some embodiments, one of R¹ and R² is H and the other is methyl.

In some embodiments, each R^(A) is independently selected from C₁₋₆alkyl, OR^(a1), C(O)R^(b1), NR^(c1)R^(d1), and S(O)₂R^(b1); wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from Cy¹, Cy¹—C₁₋₄ alkyl, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1) NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments, each R^(A) is independently selected from C₁₋₆alkyl, halo, C₁₋₆ haloalkyl, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), NR^(c1)R^(d1), S(O)₂R^(b1), 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl and5-10 membered heteroaryl-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₁₋₆haloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from Cy¹, Cy¹—C₁₋₄ alkyl, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1) NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments, each R^(A) is independently selected from halo,C₁₋₆ haloalkyl, OR^(a1), C(O)NR^(c1)R^(d1), and C(O)OR^(a1).

In some embodiments, R^(A) is OR^(a1).

In some embodiments, each R^(A) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, CN,OR^(a1), NR^(c1)R^(d1), C(O)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),C(O)R^(b1), C(O)OR^(a1), and S(O)₂R^(b1), wherein said C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,and 4-10 membered heterocycloalkyl-C₁₋₄ alkyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom halo, CN, OR^(a1), NR^(c1)R^(d1), C(O)R^(b1), andNR^(c1)C(O)R^(b1).

In some embodiments, each R^(W), R^(X), R^(Y), and R^(Z) isindependently selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, CN, OR^(a2), C(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), and NR^(c2)S(O)₂NR^(c2)R^(d2);wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, and C₆₋₁₀ aryl-C₁₋₄ alkyl of R^(W), R^(X),R^(Y), and R^(Z) are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from Cy², Cy²—C₁₋₄ alkyl, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2) NR^(c2)R^(d2) NR^(c2)C(O)R^(b2)NR^(c2)C(O)OR^(a2) NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2)NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, each R^(W), R^(X), R^(Y), and R^(Z) isindependently selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, CN, OR^(a2), C(O)NR^(c2)R^(d2), NR^(c2)R^(d2), andNR^(c2)C(O)R^(b2); wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, and C₆₋₁₀ aryl-C₁₋₄alkyl of R^(W), R^(X), R^(Y), and R^(Z) are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from Cy²,Cy²—C₁₋₄ alkyl, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2) NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In some embodiments, W is CR^(W) and R^(W) is other than H.

In some embodiments, W is CR^(W) and R^(W) is H.

In some embodiments, R^(W) is halo.

In some embodiments, R^(W) is F.

In some embodiments, R^(W) is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, and OR^(a2), wherein said C₁₋₆ alkyl and C₁₋₆ haloalkyl are eachoptionally substituted with OR^(a2).

In some embodiments, R^(W) is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, halo, and OR^(a2), wherein said C₁₋₆ alkyl and C₁₋₆ haloalkyl areeach optionally substituted with OR^(Z).

In some embodiments, R^(X) and R^(Z) are not both halogen.

In some embodiments, R^(Z) is H.

In some embodiments, when W is CR^(W), X is CR^(X), Y is CR^(Y), and Zis CR^(Z) and when m is 1 or 2, then R^(X) and R^(Y) are not both C₁₋₆alkoxy.

In some embodiments, when W is CR^(W), X is CR^(X), Y is CR^(Y), and Zis CR^(Z) and when m is 1 or 2, then R^(X) and R^(Y) are not the same.

In some embodiments, X is CR^(X) and R^(X) is other than H.

In some embodiments, X is CR^(X) and R^(X) is H.

In some embodiments, R^(X) is selected from C₁₋₆ alkyl, halo, andOR^(a2).

In some embodiments, Y is CR^(Y) and R^(Y) is other than H.

In some embodiments, Y is CR^(Y) and R^(Y) is H.

In some embodiments, Y is CR^(Y) and R^(Y) is independently selectedfrom NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2) NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),and NR^(c2)S(O)₂NR^(c2)R^(d2).

In some embodiments, Y is CR^(Y) and R^(Y) is independently selectedfrom C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2) NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2)NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), and NR^(c2)S(O)₂NR^(c2)R^(d2).

In some embodiments, Y is CR^(Y) and R^(Y) is independently selectedfrom NR^(c2)R^(d2) and NR^(c2)C(O)R^(b2).

In some embodiments, R^(Y) is independently selected from C₁₋₆ alkyl,C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, halo, CN, OR^(a2), SR^(a2), C(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2) S(O)R^(b2), NR^(c2)S(O)₂R^(b2), and NR^(c2)S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl,C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of R^(Y) are each optionally substituted with 1, 2, 3,4, or 5 substituents independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a2), NR^(c2)R^(d2), and S(O)₂R^(b2).

In some embodiments, Y is CR^(Y) and R^(Y) is independently selectedfrom C₁₋₆ alkyl and OR^(a2).

In some embodiments, Y is CR^(Y) and R^(Y) is OR^(a2).

In some embodiments, Z is CR^(Z) and R^(Z) is other than H.

In some embodiments, Z is CR^(Z) and R^(Z) is H.

In some embodiments, Z is CR^(Z) and R^(Z) is C₁₋₆ alkyl.

In some embodiments, Z is CR^(Z) and R^(Z) is C₁₋₆ alkyl, halo, or CN.

In some embodiments, each R^(a1), R^(b1), R^(c1), R^(d1), R^(a2),R^(b2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆ alkyl,and C₁₋₆ haloalkyl, wherein the C₁₋₆ alkyl is optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from Cy³,Cy³—C₁₋₄ alkyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3) NR^(c3)C(O)R^(b3), NR^(c3)C(O)NR^(c3)R^(d3),NR^(c3)C(O)OR^(a3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), andS(O)₂NR^(c3)R^(d3).

In some embodiments, each R^(a1), R^(b1), R^(c1), R^(d1), R^(a2),R^(b2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆ alkyl,and C₁₋₆ haloalkyl.

In some embodiments, each R^(a1), R^(b1), R^(c1), R^(d1), R^(a2),R^(b2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, and4-10 membered heterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, halo, CN, OR^(a3), C(O)R^(b3), C(O)OR^(a3) and S(O)₂R^(b3).

In some embodiments, R^(a2) is selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, halo, CN, OR^(a3), C(O)R^(b3), C(O)OR^(a3) and S(O)₂R^(b3).

In some embodiments, R^(c2) and R^(d2) are each independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, and 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, and4-10 membered heterocycloalkyl-C₁₋₄ alkyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, OR^(a3), C(O)R^(b3),C(O)OR^(a3) and S(O)₂R^(b3).

In some embodiments, Cy³ is 4-10 membered heterocycloalkyl optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, OR^(a3), C(O)R^(b3),C(O)OR^(a3) and S(O)₂R^(b3).

In some embodiments, Cy³ is 4-10 membered heterocycloalkyl optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C(O)R^(b3).

In some embodiments, Cy³ is piperidinyl optionally substituted with 1,2, 3, 4, or 5 substituents independently selected from halo and C(O)CH₃.

In some embodiments, the compounds of the invention have Formula II:

In some embodiments, the compounds of the invention have Formula IIIA,IIIB, IIIC, IIID, or IIIE:

In some embodiments, the compounds of the invention have Formula IVA orIVB:

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

At various places in the present specification various aryl, heteroaryl,cycloalkyl, and heterocycloalkyl rings are described. Unless otherwisespecified, these rings can be attached to the rest of the molecule atany ring member as permitted by valency. For example, the term“pyridinyl,” “pyridyl,” or “a pyridine ring” may refer to apyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

The term “n-membered,” where “n” is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is “n”. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted.

As used herein, the term “substituted” means that a hydrogen atom isreplaced by a non-hydrogen group. It is to be understood thatsubstitution at a given atom is limited by valency.

As used herein, the term “C_(i-j),” where i and j are integers, employedin combination with a chemical group, designates a range of the numberof carbon atoms in the chemical group with i-j defining the range. Forexample, C₁₋₆ alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6carbon atoms.

As used herein, the term “alkyl,” employed alone or in combination withother terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched. In some embodiments, the alkyl groupcontains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples ofalkyl moieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl, n-heptyl, and the like. In some embodiments, thealkyl group is methyl, ethyl, or propyl.

As used herein, “alkenyl,” employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon doublebonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4carbon atoms. Example alkenyl groups include, but are not limited to,ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “alkynyl,” employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon triplebonds. Example alkynyl groups include, but are not limited to, ethynyl,propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynylmoiety contains 2 to 6 or 2 to 4 carbon atoms.

As used herein, “halo” or “halogen”, employed alone or in combinationwith other terms, includes fluoro, chloro, bromo, and iodo. In someembodiments, halo is F or C₁.

As used herein, the term “haloalkyl,” employed alone or in combinationwith other terms, refers to an alkyl group having up to the full valencyof halogen atom substituents, which may either be the same or different.In some embodiments, the halogen atoms are fluoro atoms. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Examplehaloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅, and thelike.

As used herein, the term “alkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-alkyl. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms.

As used herein, “haloalkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-(haloalkyl). In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Anexample haloalkoxy group is —OCF₃.

As used herein, “amino,” employed alone or in combination with otherterms, refers to NH₂.

As used herein, the term “alkylamino,” employed alone or in combinationwith other terms, refers to a group of formula —NH(alkyl). In someembodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms.Example alkylamino groups include methylamino, ethylamino, propylamino(e.g., n-propylamino and isopropylamino), and the like.

As used herein, the term “dialkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂.Example dialkylamino groups include dimethylamino, diethylamino,dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and thelike. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms.

As used herein, the term “cycloalkyl,” employed alone or in combinationwith other terms, refers to a non-aromatic cyclic hydrocarbon includingcyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono-or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings)ring systems. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings (e.g., aryl or heteroaryl rings)fused (i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo derivatives of cyclopentane, cyclohexene, cyclohexane,and the like, or pyrido derivatives of cyclopentane or cyclohexane.Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo. Cycloalkyl groups also include cycloalkylidenes. Theterm “cycloalkyl” also includes bridgehead cycloalkyl groups (e.g.,non-aromatic cyclic hydrocarbon moieties containing at least onebridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups(e.g., non-aromatic hydrocarbon moieties containing at least two ringsfused at a single carbon atom, such as spiro[2.5]octane and the like).In some embodiments, the cycloalkyl group has 3 to 10 ring members, or 3to 7 ring members. In some embodiments, the cycloalkyl group ismonocyclic or bicyclic. In some embodiments, the cycloalkyl group ismonocyclic. In some embodiments, the cycloalkyl group is a C₃₋₇monocyclic cycloalkyl group. Example cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl,octahydronaphthalenyl, indanyl, and the like. In some embodiments, thecycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “cycloalkylalkyl,” employed alone or incombination with other terms, refers to a group of formulacycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkylportion is methylene. In some embodiments, the cycloalkyl portion has 3to 10 ring members or 3 to 7 ring members. In some embodiments, thecycloalkyl group is monocyclic or bicyclic. In some embodiments, thecycloalkyl portion is monocyclic. In some embodiments, the cycloalkylportion is a C₃₋₇ monocyclic cycloalkyl group.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic ring or ringsystem, which may optionally contain one or more alkenylene oralkynylene groups as part of the ring structure, which has at least oneheteroatom ring member independently selected from nitrogen, sulfur,oxygen, and phosphorus. Heterocycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ringsystems. In some embodiments, the heterocycloalkyl group is a monocyclicor bicyclic group having 1, 2, 3, or 4 heteroatoms independentlyselected from nitrogen, sulfur and oxygen. Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having abond in common with) to the non-aromatic heterocycloalkyl ring, forexample, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkylgroups can also include bridgehead heterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least one bridgehead atom, such asazaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least two rings fused at a singleatom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). Insome embodiments, the heterocycloalkyl group has 3 to 10 ring-formingatoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring forming atoms.In some embodiments, the heterocycloalkyl group has 2 to 20 carbonatoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2heteroatoms. The carbon atoms or heteroatoms in the ring(s) of theheterocycloalkyl group can be oxidized to form a carbonyl, an N-oxide,or a sulfonyl group (or other oxidized linkage) or a nitrogen atom canbe quaternized. In some embodiments, the heterocycloalkyl portion is aC₂₋₇ monocyclic heterocycloalkyl group. In some embodiments, theheterocycloalkyl group is a morpholine ring, pyrrolidine ring,piperazine ring, piperidine ring, tetrahydropyran ring,tetrahyropyridine, azetidine ring, or tetrahydrofuran ring.

As used herein, the term “heterocycloalkylalkyl,” employed alone or incombination with other terms, refers to a group of formulaheterocycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkylportion is methylene. In some embodiments, the heterocycloalkyl portionhas 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members.In some embodiments, the heterocycloalkyl group is monocyclic orbicyclic. In some embodiments, the heterocycloalkyl portion ismonocyclic. In some embodiments, the heterocycloalkyl portion is a C₂₋₇monocyclic heterocycloalkyl group.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., a fused ringsystem) aromatic hydrocarbon moiety, such as, but not limited to,phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, arylgroups have from 6 to 10 carbon atoms or 6 carbon atoms. In someembodiments, the aryl group is a monocyclic or bicyclic group. In someembodiments, the aryl group is phenyl or naphthyl.

As used herein, the term “arylalkyl,” employed alone or in combinationwith other terms, refers to a group of formula aryl-alkyl-. In someembodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbonatom(s). In some embodiments, the alkyl portion is methylene. In someembodiments, the aryl portion is phenyl. In some embodiments, the arylgroup is a monocyclic or bicyclic group. In some embodiments, thearylalkyl group is benzyl.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., a fusedring system) aromatic hydrocarbon moiety, having one or more heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl group is a monocyclic or a bicyclicgroup having 1, 2, 3, or 4 heteroatoms independently selected fromnitrogen, sulfur and oxygen. Example heteroaryl groups include, but arenot limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl,benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl,triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl,quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl orthe like. The carbon atoms or heteroatoms in the ring(s) of theheteroaryl group can be oxidized to form a carbonyl, an N-oxide, or asulfonyl group (or other oxidized linkage) or a nitrogen atom can bequaternized, provided the aromatic nature of the ring is preserved. Insome embodiments, the heteroaryl group has from 3 to 10 carbon atoms,from 3 to 8 carbon atoms, from 3 to 5 carbon atoms, from 1 to 5 carbonatoms, or from 5 to 10 carbon atoms. In some embodiments, the heteroarylgroup contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-formingatoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or1 to 2 heteroatoms.

As used herein, the term “heteroarylalkyl,” employed alone or incombination with other terms, refers to a group of formulaheteroaryl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkylportion is methylene. In some embodiments, the heteroaryl portion is amonocyclic or bicyclic group having 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl portion has 5 to 10 carbon atoms.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Geometric isomers of olefins,C═N double bonds, and the like can also be present in the compoundsdescribed herein, and all such stable isomers are contemplated in thepresent invention. Cis and trans geometric isomers of the compounds ofthe present invention may be isolated as a mixture of isomers or asseparated isomeric forms.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine -imine pairs, and annular formswhere a proton can occupy two or more positions of a heterocyclicsystem, for example, 1H- and 3H-imidazole, 1H-, 2H- and4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention also include all isotopes of atoms occurringin the intermediates or final compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. For example,isotopes of hydrogen include tritium and deuterium. In some embodiments,the compounds of the invention include at least one deuterium atom.

The term “compound,” as used herein, is meant to include allstereoisomers, geometric iosomers, tautomers, and isotopes of thestructures depicted, unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,in the form of hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the non-toxic salts ofthe parent compound formed, for example, from non-toxic inorganic ororganic acids. The pharmaceutically acceptable salts of the presentinvention can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature,” “room temperature,” and “r.t.”,as used herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds of the invention can be prepared according to numerouspreparatory routes known in the literature. Example synthetic methodsfor preparing compounds of the invention are provided in the Schemesbelow.

Scheme 1 shows a general synthesis of quinazolinone compounds of theinvention. Substituted aminobenzoic acids (1-A), many of which arecommercially available or can be made via routes known to one skilled inthe art, can be converted to chloromethylquinazolinones (1-B) bytreatment with chloroacetonitrile in the presence of a pre-preparedsolution of a metal such as sodium in a protic solvent such as methanolat room temperature (Step 1). The chloro group of 1-B can be convertedto a thioacetate (1-C) by treatment with thioacetic acid in a polarsolvent such as DMF at room temperature (Step 2). Introduction ofheterocycles (ring A) can be done by treatment with an appropriateelectrophile (1-D), where Lv is an appropriate leaving group such as Br,I, methanesulfonate, or para-toluenesulfonate, in the presence of a basesuch as aqueous sodium hydroxide in a polar solvent such as DMF atelevated temperature such as 90° C. (Step 3). Alternatively,quinazolinones of the invention can be prepared fromchloromethylquinazolinones (1-B) by treatment with athioacetate-substituted heterocycle or trans-4-mercaptocyclohexanol inthe presence of a base such as aqueous sodium hydroxide in a polarsolvent such as DMF at room temperature (Step 4).

Scheme 2 shows that substituted chloromethylquinazolinone intermediates(1-B) can also be prepared from substituted aminobenzoic acids (1-A)first by conversion to esters (2-A), such as where R is C₁₋₆ alkyl suchas methyl, by treatment with R-Lv, where Lv is a leaving group such asiodide, in the presence of a base such as potassium carbonate in a polarsolvent such as DMF at an appropriate temperature such as 0° C. (Step1). Many esters (2-A) can also be purchased commercially. Treatment ofesters with chloroacetonitrile in the presence of an acid such ashydrochloric acid in a solvent such as dioxane at an appropriatetemperature such as 50° C. (Step 2) yields chloromethylquinazolinones(1-B) that can then be further converted to compounds of the inventionas depicted in Scheme 1.

Scheme 3 illustrates that functionalization of the starting brominatedester (e.g., where one of W, X, Y, and Z is C—Br) can be achieved bypalladium-mediated couplings such as Suzuki reactions to preparearomatic ring-substituted derivatives (Ar refers to an aromatic ringwhich is or may be further derivatized). Alternatively, a nitrilesubstituent can be introduced via treatment of the starting brominatedester with CuCN in a polar solvent such as NMP at an elevatedtemperature such as 180° C. Functionalized esters can then be convertedto chloromethylquinazolinones as illustrated in Scheme 2.

Scheme 4 shows that an amino group can be introduced by treatment of afluorinated derivative (e.g., where one of W, X, Y, and Z is C—F) withexcess amine (R′R″NH, where R′ and R″ can be, for example, variousgroups defined by R^(c2) and R^(d2)) at an appropriate elevatedtemperature such as 120° C.

Scheme 5 shows that an amino substituent may also be introduced bytreatment of a 2-amino-4-fluorobenzoate (e.g., where one of W, X, Y, andZ is C—F) with an amine in a polar solvent such as DMSO at elevatedtemperature such as 80° C.

Scheme 6 shows that an amino substituent may be introduced by treatmentof a brominated starting material with a base such as LiHMDS and SEMClin an ethereal solvent such as THF at an appropriate temperature such as0° C. (Step 1). This reaction can be followed by coupling with amines(R′R″NH), for example, in the presence of a palladium catalyst such asPd₂(dba)₃, a phosphine ligand such as BINAP, a base such as t-BuONa, ina non-polar solvent such as toluene at an elevated temperature such as110° C. (Step 2). The SEM protecting group can then be removed bytreatment with an acid such as HCl in a polar solvent such as dioxane atslightly elevated temperature such as 40° C. (Step 3).

Scheme 7 shows that an alcohol functionality can be introduced to theSEM protected brominated quinazolinone by treatment first with potassiumhydroxide in the presence of a palladium catalyst such as Pd₂(dba)₃ anda phosphine ligand such as t-BuXPhos in a solvent such as a mixture ofdioxane and water at elevated temperature such as 90° C., followed byaddition of an electrophile such as an alkyl bromide along withtetrabutylammonium bromide and stirring at room temperature (Step 1, Lvis a leaving group and R is an alkyl group or other group selected fromR^(a2)). Removal of the SEM group can be achieved by treatment with anacid such as HCl (Step 2).

Scheme 8 summarizes preparation of amide compounds (R is, e.g.,optionally substituted alkyl or optionally substituted ring structures).Nitro derivatives can be reduced to the amine derivatives by treatmentwith a reducing agent such as iron in the presence of ammonium chloridein a mixture of water with a protic solvent such as ethanol at elevatedtemperature such as 80° C. The resulting amine can then be converted toan amide by treatment with an acyl chloride (having the appropriate Rgroup) in the presence of an amine base such as triethylamine in anon-polar solvent such as DCM at room temperature.

Scheme 9 summarizes preparation of carboxamides by treatment ofcarboxylic acid derivatives with an amine in the presence of an amidecoupling reagent such as EDCI along with HOBt in polar solvent such asDMF at room temperature.

Non-hydrogen R substituents can be introduced by the two-step procedurein Scheme 10. An appropriately substituted 2-methylaniline (10-1) can betreated with chloral hydrate, sodium sulfate and HCl in water, followedby addition of hydroxylamine and heating at 70° C. to give themethylindoline-2,3-dione intermediate (10-2, Step 1). Conversion to theaminobenzoic acid (10-3) can be achieved by treatment with hydrogenperoxide and NaOH in water at 50° C. (Step 2). The resultingaminobenzoic acids can then be converted to chloromethylquinazolinonesusing the methods described above.

Scheme 11 shows that the thioacetate intermediates of Scheme 1, Step 4can be prepared from suitable electrophiles such as bromides, iodides,methanesulfonates, or para-toluenesulfonates by treatment of theelectrophiles with potassium thioacetate in a polar solvent such as DMFat room temperature. In cases where Lv=methanesulfonate orpara-toluenesulfonate, the sulfonate group may be installed from thecorresponding alcohol by treatment of the alcohols with the appropriatesulfonyl chloride and an amine base such as triethylamine indichloromethane at 0° C. with warming to ambient temperature.

Scheme 12 shows that when Ring A contains a Boc-protected cyclic amineit can first be deprotected by treatment with acid to reveal a freeamine, which can then be further functionalized. A representativesampling of such modifications, which includes reductive aminationreactions, amide coupling reactions, and sulfonylation reactions, isillustrated.

Scheme 13 summarizes methods for preparing substitutedcyclohexylthioethers. The thioacetate 1-C from Scheme 1 can be coupledwith 1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate in the presence of abase such as sodium hydroxide (Step 1). The acetal can be removed bytreatment with an acid such as HCl in a polar solvent such as THF atroom temperature (Step 2). The resulting ketone can then be furtherfunctionalized by reduction with a hydride source such as sodiumborohydride in a protic solvent such as methanol at room temperature(Step 3). Alternatively, the ketone can be converted to an amine viareductive amination, for example by treatment with an amine in thepresence of a hydride source such as sodium cyanoborohydride in a polarsolvent such as THF at room temperature (Step 4).

Scheme 14 summarizes methods for preparing substitutedcyclohexylthioethers. A chloromethylquinazolinone (Scheme 1) can becoupled withS-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)ethanethioate inthe presence of sodium hydroxide to provide the desired thioether (Step1). Removal of the TBS group with a fluoride source such as TBAF in apolar solvent such as THF at an elevated temperature such as 50° C.provides the primary alcohol (Step 2). The alcohol can be converted to amethanesulfonate by treating with methanesulfonyl chloride in thepresence of an amine base such as triethylamine in a nonpolar solventsuch as DCM at room temperature (Step 3). The methanesulfonate can thenbe replaced with secondary amines in the presence of a tertiary aminebase such as triethylamine in a polar solvent such as THF at elevatedtemperature such as 100° C. (Step 4). Alternatively the mesylate can beconverted to a primary amine, first by treatment with sodium azide in apolar solvent such as DMF at 50° C., followed by treatment withtriphenylphosphine in a THF/water mixture at room temperature (Steps 5and 6).

Methods of Use

Compounds of the invention can inhibit the activity of PARP14. Forexample, the compounds of the invention can be used to inhibit activityof PARP14 in a cell or in an individual or patient in need of inhibitionof the enzyme by administering an inhibiting amount of a compound of theinvention to the cell, individual, or patient.

The compounds of the invention can further inhibit the production ofIL-10 in a cell. For example, the present invention relates to methodsof inhibiting or decreasing the production of IL-10 in a cell bycontacting the cell with a PARP14 inhibitor of the invention.

As PARP14 inhibitors, the compounds of the invention are useful in thetreatment of various diseases associated with abnormal expression oractivity of PARP14. For example, the compounds of the invention areuseful in the treatment of cancer. In some embodiments, the cancerstreatable according to the present invention include hematopoieticmalignancies such as leukemia and lymphoma. Example lymphomas includeHodgkin's or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma(e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocyticlymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkett'slymphoma. Example leukemias include acute lymphocytic leukemia (ALL),acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL),and chronic myelogenous leukemia (CML).

Other cancers treatable by the administration of the compounds of theinvention include liver cancer (e.g., hepatocellular carcinoma), bladdercancer, bone cancer, glioma, breast cancer, cervical cancer, coloncancer, endometrial cancer, epithelial cancer, esophageal cancer,Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer,gastrointestinal tumors, head and neck cancer, intestinal cancers,Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g.,hepatocellular carcinoma), lung cancer, prostate cancer, rectal cancer,skin cancer, stomach cancer, testicular cancer, thyroid cancer, anduterine cancer.

In some embodiments, the cancer treatable by administration of thecompounds of the invention is multiple myeloma, DLBCL, hepatocellularcarcinoma, bladder cancer, esophageal cancer, head and neck cancer,kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroidcancer, uterine cancer, breast cancer, glioma, follicular lymphoma,pancreatic cancer, lung cancer, colon cancer, or melanoma.

The PARP14 inhibitors of the invention may also have therapeutic utilityin PARP14-related disorders in disease areas such as cardiology,virology, neurodegeneration, inflammation, and pain, particularly wherethe diseases are characterized by overexpression or increased activityof PARP14.

In some embodiments, the compounds of the invention are useful in thetreatment of an inflammatory disease. In some embodiments, theinflammatory diseases treatable according to the present inventioninclude inflammatory bowel diseases (e.g., Crohn's disease or ulcerativecolitis), inflammatory arthritis, inflammatory demyelinating disease,psoriasis, allergy and asthma sepsis, allergic airway disease (e.g.,asthma), and lupus.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” PARP14 or “contacting” a cell with a compound ofthe invention includes the administration of a compound of the presentinvention to an individual or patient, such as a human, having PARP14,as well as, for example, introducing a compound of the invention into asample containing a cellular or purified preparation containing PARP14.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to mammals, and particularly humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician.

As used herein the term “treating” or “treatment” refers to 1)inhibiting the disease in an individual who is experiencing ordisplaying the pathology or symptomatology of the disease (i.e.,arresting further development of the pathology and/or symptomatology),or 2) ameliorating the disease in an individual who is experiencing ordisplaying the pathology or symptomatology of the disease (i.e.,reversing the pathology and/or symptomatology).

As used herein the term “preventing” or “prevention” refers topreventing the disease in an individual who may be predisposed to thedisease but does not yet experience or display the pathology orsymptomatology of the disease.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, chemotherapeutics or other anti-cancer agents, immuneenhancers, immunosuppressants, immunotherapies, radiation, anti-tumorand anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.),and/or kinase (tyrosine or serine/threonine), epigenetic or signaltransduction inhibitors can be used in combination with the compounds ofthe present invention. The agents can be combined with the presentcompounds in a single dosage form, or the agents can be administeredsimultaneously or sequentially as separate dosage forms.

Suitable agents for use in combination with the compounds of the presentinvention for the treatment of cancer include chemotherapeutic agents,targeted cancer therapies, immunotherapies or radiation therapy.Compounds of this invention may be effective in combination withanti-hormonal agents for treatment of breast cancer and other tumors.Suitable examples are anti-estrogen agents including but not limited totamoxifen and toremifene, aromatase inhibitors including but not limitedto letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds of the present invention. These include anti-androgensincluding but not limited to flutamide, bicalutamide, and nilutamide,luteinizing hormone-releasing hormone (LHRH) analogs includingleuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists(e.g. degarelix), androgen receptor blockers (e.g. enzalutamide) andagents that inhibit androgen production (e.g. abiraterone).

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith FGFR inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib Suitable chemotherapeutic or otheranti-cancer agents include, for example, alkylating agents (including,without limitation, nitrogen mustards, ethylenimine derivatives, alkylsulfonates, nitrosoureas and triazenes) such as uracil mustard,chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan,chlorambucil, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, and temozolomide.

Other anti-cancer agent(s) include antibody therapeutics tocostimulatory molecules such as CTLA-4, 4-1BB, PD-1, and PD-L1, orantibodies to cytokines (IL-10, TGF-β, etc.). Exemplary cancerimmunotherapy antibodies include alemtuzumab, ipilimumab, nivolumab,ofatumumab and rituximab.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Apharmaceutical composition refers to a combination of a compound of theinvention, or its pharmaceutically acceptable salt, and at least onepharmaceutically acceptable carrier. These compositions can be preparedin a manner well known in the pharmaceutical art, and can beadministered by a variety of routes, depending upon whether local orsystemic treatment is desired and upon the area to be treated.Administration may be oral, topical (including ophthalmic and to mucousmembranes including intranasal, vaginal and rectal delivery), pulmonary(e.g., by inhalation or insufflation of powders or aerosols, includingby nebulizer; intratracheal, intranasal, epidermal and transdermal),ocular, or parenteral.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

The compositions can be formulated in a unit dosage form. The term “unitdosage form” refers to a physically discrete unit suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepre-formulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid pre-formulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, anti-cancer agents,vaccines, antibodies, immune enhancers, immune suppressants,anti-inflammatory agents and the like.

EXAMPLES

Equipment: ¹H NMR Spectra were recorded at 400 MHz using a Bruker AVANCE400 MHz spectrometer. NMR interpretation was performed using MestReC orMestReNova software to assign chemical shift and multiplicity. In caseswhere two adjacent peaks of equal or unequal height were observed, thesetwo peaks may be labeled as either a multiplet or as a doublet. In thecase of a doublet, a coupling constant using this software may beassigned. In any given example, one or more protons may not be observeddue to obscurity by water and/or solvent peaks. LCMS equipment andconditions are as follows:

LC: Agilent Technologies 1290 series, Binary Pump, Diode Array Detector.Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6×50 mm column. Mobile phase: A:0.05% Formic acid in water (v/v), B: 0.05% Formic acid in ACN (v/v).Flow Rate: 1 mL/min at 25° C. Detector: 214 nm, 254 nm. Gradient stoptime, 10 min. Timetable:

T (min) A(%) B(%) 0.0 90 10 0.5 90 10 8.0 10 90 10.0 0 100

MS: G6120A, Quadrupole LC/MS, Ion Source: ES-API, TIC: 70˜1000 m/z,Fragmentor: 60, Drying gas flow: 10 L/min, Nebulizer pressure: 35 psi,Drying gas temperature: 350° C., Vcap: 3000V.

Sample preparation: samples were dissolved in ACN or methanol at 1˜10mg/mL, then filtered through a 0.22 μm filter membrane. Injectionvolume: 1˜10 μL.

Definitions: AcCl (acetyl chloride); ACN (acetonitrile); Ac₂O (aceticanhydride); AcOH (acetic acid); AcSH (thioacetic acid); atm(atmosphere); BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); BnBr (benzyl bromide); Boc (tert-butoxycarbonyl);Boc₂O (di-tert-butyl dicarbonate); CDCl₃ (deuterated chloroform); CD₃OD(deuterated methanol); conc. (concentrated); CO (carbon monoxide); dba(dibenzylideneacetone); DCM (dichloromethane); DIPEA(N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DME(1,2-dimethoxyethane); DMF (N,N-dimethylformamide); DMSO(dimethylsulfoxide); DMSO-d₆ (deuterated dimethylsulfoxide); EDCI(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); eq (equivalent); ES-API(electrospray atmospheric pressure ionization); Et₃N (triethylamine);Et₂O (diethyl ether); EtOAc (ethyl acetate); EtOH (ethanol); g (gram); h(hour); HATU(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate); HOBt (hydroxybenzotriazole); ¹H NMR(proton nuclear magnetic resonance); Hz (hertz); KSAc (potassiumthioacetate); L (litre); LCMS (liquid chromatography-mass spectrometry);LiHMDS (lithium bis(trimethylsilyl)amide); M (molar); MeOH (methanol);mg (milligrams); MHz (megahertz); min (minutes); mL (millilitres), mmol(millimoles); MsCl (methanesulfonyl chloride); n-BuLi (n-butyllithium);NMP (N-methyl-2-pyrrolidone); PhOH (phenol); prep-HPLC (preparativehigh-performance liquid chromatography); prep-TLC (preparative thinlayer chromatography); ppm (parts per million); psi (pounds per squareinch); p-TSA (p-toluenesulfonic acid); pyBOP((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate);RT (room temperature); SEM (2-(trimethylsilyl)ethoxymethyl); SEMCl(2-(trimethylsilyl)ethoxymethyl chloride); TBAF (tetra-n-butylammoniumfluoride); t-BuXPhos(2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl; TFA(trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin layerchromatography); v/v (volume/volume).

Synthesis of Intermediates Int-A1:2-(Chloromethyl)-8-methylquinazolin-4(3H)-one

Chloroacetonitrile (75 g, 0.99 mol, 3 eq) was added dropwise to apre-prepared solution of sodium (1.52 g, 6.6 mmol, 0.2 eq) in methanol(200 mL) over 10 mins at RT under a nitrogen atmosphere. After stirringfor 1 h, a solution of 2-amino-3-methylbenzoic acid (50 g, 0.33 mmol,1.0 eq) in methanol (700 mL) was added and the mixture was stirred at RTfor another 2 h. The resulting precipitate was collected by filtrationand washed with water then MeOH and dried under vacuum to give the titlecompound (46.9 g, 68%) as a white solid. LCMS: [M+H]⁺ 209.0. Thefollowing intermediates in Table 1 were similarly prepared from theappropriate amino acid starting material according to the methoddescribed for Int-A1.

TABLE 1 LCMS: Intermediate Name Amino acid [M + H]⁺

2-(Chloromethyl)-7- methylquinazolin-4(3H)-one 2-amino-4-methylbenzoicacid 209.0

2-(Chloromethyl)-6- methylquinazolin-4(3H)-one 2-amino-5-methylbenzoicacid 209.0

2-(Chloromethyl)-8- methoxyquinazolin-4(3H)-one 2-amino-3-methoxybenzoic acid 225.0

2-(Chloromethyl)-7- methoxyquinazolin-4(3H)-one 2-amino-4-methoxybenzoic acid 225.0

2-(Chloromethyl)-6- methoxyquinazolin-4(3H)-one 2-amino-5-methoxybenzoic acid 225.0

8-Chloro-2- (chloromethyl)quinazolin- 4(3H)-one 2-amino-3-chlorobenzoicacid 229.0

7-Bromo-2- (chloromethyl)quinazolin- 4(3H)-one 2-amino-4-bromobenzoicacid 272.9

2-(Chloromethyl)-7- fluoroquinazolin-4(3H)-one 2-amino-4-fluorobenzoicacid 213.0

2-(Chloromethyl)-7- (trifluoromethyl)quinazolin- 4(3H)-one 2-amino-4-(trifluoromethyl)benzoic acid 263.0

2-(Chloromethyl)-7- nitroquinazolin-4(3H)-one 2-amino-4-nitrobenzoicacid 240.0

2-(Chloromethyl)-6,8- dimethylquinazolin-4(3H)-one 2-amino-3,5-dimethylbenzoic acid 223.1

6-Chloro-2-(chloromethyl)-8- methylquinazolin-4(3H)-one2-amino-5-chloro-3- methylbenzoic acid 243.0

6-Bromo-2-(chloromethyl)-8- methylquinazolin-4(3H)-one2-amino-5-bromo-3- methylbenzoic acid 287.0

2-(Chloromethyl)-5- methylquinazolin-4(3H)-one 2-amino-6-methylbenzoicacid 209.0

Int-A16: Methyl2-(chloromethyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate

Chloroacetonitrile (9 g, 120 mmol, 5 eq) and dimethyl2-aminoterephthalate (5 g, 23.9 mmol, 1.0 eq) were dissolved in a 4.5 MHCl/dioxane solution (80 mL) and the mixture was heated at 50° C. for 3h under a N₂ atmosphere. The mixture was cooled to RT and theprecipitate was collected by filtration, washed with dioxane (10 mL) anddried under vacuum to give the title compound (6 g, 98%) as a whitesolid. LCMS: [M+H]⁺ 253.0

Int-A17: 2-(Chloromethyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile

Step 1: Ethyl 2-amino-3-bromobenzoate

To a suspension of 2-amino-3-bromobenzoic acid (1.1 g, 5.1 mmol, 1.0 eq)and Cs₂CO₃ (3.3 g, 10.2 mmol, 2 eq) in DMF (10 mL) at 0° C. was addedEtI (0.95 g, 6.1 mmol, 1.2 eq) dropwise. The mixture was then allowed towarm to RT and stirred for 16 h. The mixture was poured into water (20mL) and extracted with EtOAc (20 mL×3). The organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by column chromatography (Petroleum ether:EtOAc, 50:1, v/v) toafford the title compound (820 mg, 68%) as a white solid. LCMS: [M+H]⁺244.1.

Step 2: Ethyl 2-amino-3-cyanobenzoate

To a solution of ethyl 2-amino-3-bromobenzoate (340 mg, 1.4 mmol, 1.0eq) in NMP (4 mL) was added CuCN (251 mg, 2.8 mmol, 2.0 eq) and themixture was heated at 180° C. for 4 h. After cooling to RT, water (20mL) was added and the mixture was extracted with EtOAc (20 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography(Petroleum ether:EtOAc, 10:1, v/v) to afford the title compound (170 mg,64%) as a white solid. LCMS: [M+H]⁺ 191.3.

Step 3: 2-(Chloromethyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile

The title compound was prepared from ethyl 2-amino-3-cyanobenzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 220.2.

Int-A18: 2-(Chloromethyl)-4-oxo-3,4-dihydroquinazoline-7-carbonitrile

The title compound was prepared from 2-amino-4-bromobenzoic acidaccording to the method described for Int-A17. LCMS: [M+H]⁺ 220.1.

Int-A19: 2-(Chloromethyl)-7-phenoxyquinazolin-4(3H)-one

Step 1: Methyl 2-nitro-4-phenoxybenzoate

To a solution of methyl 4-fluoro-2-nitrobenzoate (1.0 g, 5 mmol, 1.0 eq)and PhOH (0.79 g, 7.5 mmol, 1.5 eq) in DMSO (10 mL) was added K₂CO₃(1.38 g, 10 mmol, 2 eq) and the mixture was heated at 90° C. for 2 h.After cooling to RT, water (50 mL) was added and the mixture wasextracted with EtOAc (60 mL×3). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by column chromatography (Petroleum ether:EtOAc, 25:1, v/v) toafford the title compound (1.2 g, 88%) as a white solid, which was useddirectly in the next step.

Step 2: Methyl 2-amino-4-phenoxybenzoate

To a solution of methyl 2-nitro-4-phenoxybenzoate (1.2 g, 4.4 mmol) inEtOAc (20 mL) was added Pd(OH)₂/C (1.2 g, 5% wet) and the mixture wasstirred at RT under a H₂ atmosphere (1 atm) overnight. The mixture wasfiltered and the filtrate was concentrated under reduced pressure togive the title compound (1.15 g, 100%), which was used for the next stepwithout further purification. LCMS: [M+H]⁺ 244.1.

Step 3: 2-(Chloromethyl)-7-phenoxyquinazolin-4(3H)-one

The title compound was prepared from methyl 2-amino-4-phenoxybenzoateand chloroacetonitrile according to the method described for Int-A16.LCMS: [M+H]⁺ 287.1.

Int-A20:2-(Chloromethyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one

Step 1: 7-Methyl-4-(trifluoromethyl)indoline-2,3-dione

To a solution of chloral hydrate (4.4 g, 26.4 mmol, 1.1 eq) and Na₂SO₄(13.6 g) in water (20 mL) was added a solution of2-methyl-5-(trifluoromethyl)aniline (4.2 g, 24 mmol, 1.0 eq) in conc.HCl (2.5 mL) dropwise followed by a solution of hydroxylaminehydrochloride (5.46 g) in water (20 mL). The mixture was then heated at70° C. for 6 h, then allowed to cool to RT and filtered. The filter cakewas washed with water (20 mL×3) and dried to give the title compound (2g, 36%). LCMS: [M+H]⁺ 247.3.

Step 2: 2-Amino-3-methyl-6-(trifluoromethyl)benzoic Acid

To a solution of 7-methyl-4-(trifluoromethyl)indoline-2,3-dione (500 mg,2.2 mmol, 1.0 eq) in 2 M NaOH (2.5 mL, 2.3 eq) was added H₂O₂ (30%, 0.6mL) and the mixture was heated at 50° C. overnight. The mixture wascooled to RT, diluted with water (5 mL) and adjusted to pH 6-7 with 1 MHCl. The resulting solid was collected by filtration, washed with water(10 mL×2) and dried to give the title compound (450 mg, 86%) as a brownsolid. LCMS: [M+H]⁺ 220.1.

Step 3: Methyl 2-amino-3-methyl-6-(trifluoromethyl)benzoate

To a suspension of 2-amino-3-methyl-6-(trifluoromethyl)benzoic Acid (1.0g, 4.4 mmol, 1.0 eq) and K₂CO₃ (1.2 g, 8.8 mmol, 2 eq) in DMF (20 mL) at0° C. was added MeI (0.9 g, 6.1 mmol, 1.5 eq) dropwise and the mixturewas allowed to warm to RT and stirred for 16 h. The mixture was pouredinto water (20 mL) and extracted with EtOAc (30 mL×3). The combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (Petroleumether:EtOAc, 50:1, v/v) to afford the title compound (740 mg, 69%) as abrown oil. LCMS: [M+H]⁺ 234.2.

Step 4:2-(Chloromethyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one

The title compound was prepared from methyl2-amino-3-methyl-6-(trifluoromethyl)benzoate and chloroacetonitrileaccording to the method described for Int-A16. LCMS: [M+H]⁺ 277.1.

Int-A21: 2-(Chloromethyl)-5-fluoro-8-methylquinazolin-4(3H)-one

The title compound was prepared from 4-fluoro-7-methylindoline-2,3-dioneaccording to the method described for Int-A20 steps 2, 3, 4. LCMS:[M+H]⁺ 227.1.

Int-A22: 5-Chloro-2-(chloromethyl)-8-methylquinazolin-4(3H)-one

The title compound was prepared from 5-chloro-2-methylaniline accordingto the methods described for Int-A20. LCMS: [M+H]⁺ 243.0.

Int-A23: 2-(Chloromethyl)-7-fluoro-8-methylquinazolin-4(3H)-one

Step 1: Methyl 2-amino-4-fluoro-3-methylbenzoate

The title compound was prepared from 2-amino-4-fluoro-3-methylbenzoicacid according to the method described for Int-A20, step 3. LCMS: [M+H]⁺184.1.

Step 2: 2-(Chloromethyl)-7-fluoro-8-methylquinazolin-4(3H)-one

The title compound was prepared from methyl2-amino-4-fluoro-3-methylbenzoate and chloroacetonitrile according tothe method described for Int-A16. LCMS: [M+H]⁺ 227.1.

Int-A24: 7-Bromo-2-(chloromethyl)-8-methylquinazolin-4(3H)-one

Step 1: Methyl 2-amino-4-bromo-3-methylbenzoate

The title compound was prepared from 2-amino-4-bromo-3-methylbenzoicacid according to the method described for Int-A20, step 3. LCMS: [M+H]⁺229.9.

Step 2. 2-(Chloromethyl)-7-bromo-8-methylquinazolin-4(3H)-one

The title compound was prepared from methyl2-amino-4-bromo-3-methylbenzoate and chloroacetonitrile according to themethod described for Int-A16. LCMS: [M+H]⁺ 286.9.

Int-A25: 2-(Chloromethyl)-7,8-difluoroquinazolin-4(3H)-one

Step 1: Methyl 2-amino-3,4-difluorobenzoate

The title compound was prepared from 2-amino-3,4-difluorobenzoic acidaccording to the method described for Int-A20, step 3. LCMS: [M+H]⁺188.1.

Step 2. 2-(Chloromethyl)-7,8-difluoroquinazolin-4(3H)-one

The title compound was prepared from methyl 2-amino-3,4-difluorobenzoateand chloroacetonitrile according to the method described for Int-A16.LCMS: [M+H]⁺ 231.0.

Int-A26: 7,8-Dichloro-2-(chloromethyl)quinazolin-4(3H)-one

Step 1: Methyl 2-amino-3,4-dichlorobenzoate

The title compound was prepared from 2-amino-3,4-dichlorobenzoic acidaccording to the method described for Int-A20, step 3. LCMS: [M+H]⁺220.0.

Step 2: 7,8-Dichloro-2-(chloromethyl)quinazolin-4(3H)-one

The title compound was prepared from methyl 2-amino-3,4-dichlorobenzoateand chloroacetonitrile according to the method described for Int-A16.LCMS: [M+H]⁺ 263.0.

Int-A27: 2-(Chloromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one

The title compound was prepared from methyl 3-aminopicolinate andchloroacetonitrile according to the method described for Int-A16 but at120° C. in a microwave for 1 h. LCMS: [M+H]⁺ 196.0.

Int-A28: 2-(Chloromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was prepared from methyl 3-aminoisonicotinate andchloroacetonitrile according to the method described for Int-A16 but at120° C. in a microwave for 1 h. LCMS: [M+H]⁺ 196.0.

Int-A29: 2-(Chloromethyl)-8-methylpyrido[3,4-d]pyrimidin-4(3H)-one

Step 1: Methyl 3-amino-2-methylisonicotinate

To a solution of methyl 3-amino-2-chloroisonicotinate (2.0 g, 10.7 mmol,1.0 eq) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (4.0 g, 32.2mmol, 3.0 eq) in 1,4-dioxane (40 mL) under a N₂ atmosphere was addedPd(dppf)Cl₂ (1.6 g, 2.1 mmol, 0.2 eq) and K₂CO₃ (3.0 g, 21.4 mmol, 2.0eq) and the mixture was heated at 100° C. for 1 h in a microwave. Themixture was cooled to RT, diluted with water (50 mL) and extracted withEtOAc (50 mL×3). The combined organic layers were washed with water (40mL), dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (Petroleum ether:EtOAc,5:1 to 3:1, v/v) to afford the title compound (1.9 g, 100%) as a yellowsolid. LCMS: [M+H]⁺ 167.1.

Step 2: 2-(Chloromethyl)-8-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was prepared from methyl3-amino-2-methylisonicotinate and chloroacetonitrile according to themethod described for Int-A16 but heated at 120° C. in a sealed tube for3 days. LCMS: [M+H]⁺ 210.1.

Int-A30: 2-(Chloromethyl)-8-methylpyrido[3,2-d]pyrimidin-4(3H)-one

Step 1: Methyl 3-amino-4-methylpicolinate

To a solution of 2-bromo-4-methylpyridin-3-amine (1.0 g, 5.3 mmol) inmethanol (20 mL) was added PdCl₂(dppf) (390 mg, 5% wet) and the mixturewas heated at 70° C. under a CO atmosphere (30 atm) overnight. Themixture was cooled to RT, filtered and concentrated. The residue waspurified by column chromatography (Petroleum ether:EtOAc, 3:1, v/v) toafford the title compound (370 mg, 41%) as light yellow solid. LCMS:[M+H]⁺ 167.1.

Step 2: 2-(Chloromethyl)-8-methylpyrido[3,4-d]pyrimidin-4(3H)-one

The title compound was prepared from methyl 3-amino-4-methylpicolinateand chloroacetonitrile according to the method described for Int-A16 butheated at 100° C. in a sealed tube for 2 days. LCMS: [M+H]⁺ 210.0.

Int-A31: 2-(Chloromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one

To a mixture of 4-aminopyridine-3-carboxamide (50 mg, 0.36 mmol), DMAP(2 mg, 0.02 mmol) and DIPEA (141 mg, 1.1 mmol) was added 2-chloroacetylchloride (82 mg, 0.7 mmol, 2 eq) and the mixture was heated at 100° C.in a microwave for 10 min. The mixture was diluted with water (5 mL) andthe solid was collected by filtration to give the title compound (66 mg,93%) as a white solid. LCMS: [M+H]⁺ 196.0.

Int-A32: 2-(Chloromethyl)pyrido[2,3-d]pyrimidin-4(3H)-one

Step 1: 2-[(2-Chloroacetyl)amino]pyridine-3-carboxamide

To a solution of 2-aminopyridine-3-carboxamide (400 mg, 2.9 mmol) andpyridine (0.7 mL, 8.8 mmol) in DCM (20 mL) at 0° C. was added2-chloroacetyl chloride (362 mg, 3.2 mmol, 1.1 eq) dropwise. The mixturewas stirred at 0° C. for 1 h then allowed to warm to RT and stirredovernight. The mixture was poured into water (20 mL) and extracted withDCM (20 mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (Petroleum ether:EtOAc, 2:1, v/v) to afford the titlecompound (180 mg, 29%) as a black solid. LCMS: [M+H]⁺ 214.1.

Step 2: 2-(Chloromethyl)-3H-pyrido[2,3-d]pyrimidin-4-one

To a solution of 2-[(2-chloroacetyl)amino]pyridine-3-carboxamide (100mg, 0.5 mmol) in toluene (10 mL) was added p-TSA (161 mg, 0.9 mmol) andthe mixture was heated at reflux for 4 h. The mixture was thenconcentrated under reduced pressure and the residue was purified byreverse phase column (Biotage, C18 column, 30-80% ACN in water) toafford the title compound (25 mg, 27%) as a gray solid. LCMS: [M+H]⁺196.0.

Int-A33: 2-(1-Chloroethyl)-8-methylquinazolin-4(3H)-one

The title compound was prepared from 2-amino-3-methylbenzoic acid and2-chloropropanenitrile according to the method described for Int-A1.LCMS: [M+H]⁺ 223.1.

Int-A34: 2-(2-Chloroethyl)-8-methylquinazolin-4(3H)-one

The title compound was prepared from methyl 2-amino-3-methylbenzoate and3-chloropropanenitrile according to the method described for Int-A16.LCMS: [M+H]⁺ 223.1.

Int-A35: 8-Benzyl-2-(chloromethyl)quinazolin-4(3H)-one

Step 1: Ethyl 2-amino-3-benzylbenzoate

To a solution of ethyl 2-amino-3-bromobenzoate (488 mg, 2 mmol, 1.0 eq)in THF/water (24 mL, 5:1) under a N₂ atmosphere was added potassiumbenzyltrifluoroborate (400 mg, 2.0 mmol, 1.0 eq), PdCl₂(dppf) (80 mg,0.1 mmol, 0.05 eq) and Cs₂CO₃ (2.0 g, 6.1 mmol, 3.0 eq) and the mixturewas heated at 80° C. for 3 days. The mixture was cooled to RT, dilutedwith water (20 mL) and extracted with EtOAc (40 mL×3). The combinedorganic layers were washed with water (40 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (Petroleum ether:EtOAc, 10:1, v/v) to afford the titlecompound (190 mg, 28%) as a brown oil. LCMS: [M+H]⁺ 256.1.

Step 2: 8-Benzyl-2-(chloromethyl)quinazolin-4(3H)-one

The title compound was prepared from ethyl 2-amino-4-bromobenzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 285.2.

Int-A36: 7-Benzyl-2-(chloromethyl)quinazolin-4(3H)-one

The title compound was prepared from ethyl 2-amino-4-bromobenzoateaccording to the method described for Int-A35. LCMS: [M+H]⁺ 285.1.

Int-A37:2-(Chloromethyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one

Step 1: Methyl 2-amino-4,6-difluorobenzoate

The title compound was prepared from 4,6-difluoroindoline-2,3-dioneaccording to the method described for Int-A20, steps 2 and 3. LCMS:[M+H]⁺ 188.0.

Step 2: Methyl 2-amino-4-(cyclopentylamino)-6-fluorobenzoate

To a solution of methyl 2-amino-4,6-difluorobenzoate (3 g, 16.0 mmol,1.0 eq) in DMSO (5 mL) was added cyclopentanamine (2.73 g, 32.0 mmol,2.0 eq) and the mixture was heated at 80° C. overnight. The mixture wascooled to RT, diluted with water (5 mL) and extracted with DCM (40mL×2). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (Petroleum ether:DCM, 40:1, v/v to Petroleum ether:EtOAc,30:1 to 20:1, v/v) to afford the title compound (863 mg, 21%) as a redsolid. LCMS: [M+H]⁺ 253.1.

Step 3:2-(Chloromethyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one

The title compound was prepared from methyl2-amino-4-(cyclopentylamino)-6-fluorobenzoate and chloroacetonitrileaccording to the method described for Int-A16. LCMS: [M+H]⁺ 296.1.

Int-A38:2-(Chloromethyl)-7-(cyclobutylamino)-5-fluoroquinazolin-4(3H)-one

Step 1: Methyl 2-amino-4-(cyclobutylamino)-6-fluorobenzoate

The title compound was prepared from methyl 2-amino-4,6-difluorobenzoateand cyclobutanamine according to the method described for Int-A37, step2. LCMS: [M+H]⁺ 239.1.

Step 2:2-(Chloromethyl)-7-(cyclobutylamino)-5-fluoroquinazolin-4(3H)-one

The title compounds was prepared from methyl2-amino-4-(cyclobutylamino)-6-fluorobenzoate and chloroacetonitrileaccording to the method described for Int-A16. LCMS: [M+H]⁺ 282.1.

Int-B1: S-(Tetrahydro-2H-pyran-4-yl) Ethanethioate

To a solution of 4-bromotetrahydro-2H-pyran (50.0 g, 303 mmol, 1.0 eq)in DMF (300 mL) under a N₂ atmosphere was added KSAc (41.5 g, 364 mmol,1.2 eq) and the mixture was stirred at RT overnight. The mixture wasdiluted with water (700 mL) and extracted with EtOAc (200 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure to afford the title compound (41.5 g, 68%) as a brownoil.

¹H NMR (400 MHz, CDCl₃) δ 3.91-3.87 (m, 2H), 3.71-3.64 (m, 1H),3.57-3.51 (m, 2H), 2.31 (s, 3H), 1.92-1.88 (m, 2H), 1.71-1.62 (m, 2H).

Int-B2: tert-Butyl 4-(acetylthio)piperidine-1-carboxylate

The title compound was prepared from tert-butyl4-bromopiperidine-1-carboxylate according to the method described forInt-B1.

¹H NMR (400 MHz, CDCl₃) δ 3.87-3.84 (m, 2H), 3.64-3.57 (m, 1H),3.08-3.02 (m, 2H), 2.31 (s, 3H), 1.92-1.87 (m, 2H), 1.58-1.45 (m, 2H),1.45 (s, 9H).

Int-B3: S-(1-Methylpiperidin-3-yl) Ethanethioate

Step 1: 1-Methylpiperidin-3-yl Methanesulfonate

To a solution of 1-methylpiperidin-3-ol (2.0 g, 17.4 mmol, 1.0 eq) andtriethylamine (3.5 g, 34.8 mmol, 2.0 eq) in DCM (20 mL) at 0° C. wasadded methanesulfonyl chloride (2.4 g, 21 mmol, 1.2 eq) dropwise and themixture was allowed to warm to RT and stirred for 3 h. The mixture wasdiluted with DCM (120 mL) and washed with 0.5 M HCl (40 mL) and water(40 mL). The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to afford the title compound (3.3 g, 99%) as a lightyellow oil, which was used directly in the next step without furtherpurification. LCMS: [M+H]⁺ 194.1.

Step 2: S-(1-Methylpiperidin-3-yl) Ethanethioate

To a solution of 1-methylpiperidin-3-yl Methanesulfonate (1.6 g, 8.1mmol, 1.0 eq) in DMF (50 mL) under a N₂ atmosphere was added KSAc (1.1g, 9.7 mmol, 1.2 eq) and the mixture was stirred at RT overnight. Themixture was diluted with water (20 mL) and extracted with EtOAc (40mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (Petroleum ether:EtOAc, 10:1, v/v) to afford the titlecompound (1 g, 71%) as a brown oil. LCMS: [M+H]⁺ 174.1.

Int-B4: tert-Butyl 3-(acetylthio)piperidine-1-carboxylate

The title compound was prepared from tert-butyl3-hydroxypiperidine-1-carboxylate according to the method described forInt-B3. LCMS: [M+H−56]⁺203.1.

Int-B5-trans: S-(trans-4-((tert-Butoxycarbonyl)amino)cyclohexyl)Ethanethioate

and

Int-B5-cis: S-(cis-4-((tert-Butoxycarbonyl)amino)cyclohexyl)Ethanethioate

The title compound was prepared from cis trans-tert-butyl(4-hydroxycyclohexyl)carbamate according to the method described forInt-B3. Purification by column chromatography (Petroleum ether:EtOAc,1:0 to 10:1, v/v) gave the two separated isomers. Int-B5-trans: LCMS:[M+H−100]⁺ 174.1; Int-B5-cis: LCMS: [M+H−100]⁺ 174.1.

Int-B6: S-1,4-Dioxaspiro[4.5]decan-8-yl Ethanethioate

The title compound was prepared from 1,4-dioxaspiro[4.5]decan-8-olaccording to the method described for Int-B3.

¹H NMR (400 MHz, CDCl₃) δ 3.93 (s, 4H), 3.56-3.51 (m, 1H), 2.32 (s, 3H),2.00-1.96 (m, 2H), 1.77-1.65 (m, 6H).

Int-B7: S-((trans)-3-(Benzyloxy)cyclobutyl) Ethanethioate

Step 1: cis-3-(Benzyloxy)cyclobutanol

The title compound was prepared from 3-(benzyloxy)cyclobutanone (5.0 g,28.4 mmol, 1.0 eq) according to the procedure described in Bioorg. Med.Chem. 2013, 21, 643 (5.2 g, 100%) as a colorless oil, which was used forthe next step without further purification.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.28 (m, 5H), 4.42 (s, 2H), 3.95-3.88 (m,1H), 3.66-3.60 (m, 1H), 2.75-2.69 (m, 2H), 1.98-1.90 (m, 2H).

Step 2: (cis)-3-(Benzyloxy)cyclobutyl Methanesulfonate

The title compound was prepared from cis-3-(benzyloxy)cyclobutanolaccording to the procedure described for Int-B3 step 1.

¹H NMR (400 MHz, CDCl₃) δ 7.37-7.28 (m, 5H), 4.69-4.61 (m, 1H), 4.43 (s,2H), 3.77-3.70 (m, 1H), 2.98 (s, 3H), 2.86-2.81 (m, 2H), 2.37-2.30 (m,2H).

Step 3: S-(trans-3-(Benzyloxy)cyclobutyl) Ethanethioate

The title compound was prepared from (cis)-3-(benzyloxy)cyclobutylMethanesulfonate according to the method described for Int-B3 step 2.

¹H NMR (400 MHz, CDCl₃) δ 7.37-7.27 (m, 5H), 4.40 (s, 2H), 4.29-4.23 (m,1H), 4.01-3.95 (m, 1H), 2.64-2.57 (m, 2H), 2.29 (s, 3H), 2.28-2.23 (m,2H).

Int-B8: S-Oxetan-3-yl Ethanethioate

The title compound was prepared from commercially available oxetan-3-yl4-methylbenzenesulfonate according to the method described for Int-B3step 2.

¹H NMR (400 MHz, CDCl₃) δ 5.05 (t, J=7.2 Hz, 2H), 4.69-4.62 (m, 1H),4.58 (t, J=6.8 Hz, 2H), 2.33 (s, 3H).

Int-B9: S-(trans-3-((tert-Butoxycarbonyl)amino)cyclobutyl) Ethanethioate

Step 1: tert-Butyl (cis-3-hydroxycyclobutyl)carbamate

To a solution of cis-3-aminocyclobutanol hydrochloride (900 mg, 7.3mmol, 1.0 eq) in ethanol (5 mL) and Et₃N (5 mL) at 0° C. was added Boc₂O(800 mg, 3.7 mmol, 0.5 eq) and the mixture was allowed to warm to RT andstirred for 3 h. The mixture was concentrated under reduced pressure,diluted with water (50 mL) and extracted with EtOAc (40 mL×3). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound (1.2 g, 88%) as a yellow solid, which was used for the nextstep without further purification. LCMS: [M+H]⁺ 188.2.

Step 2: (cis)-3-((tert-Butoxycarbonyl)amino)cyclobutyl Methanesulfonate

The title compound was prepared from tert-butyl(cis-3-hydroxycyclobutyl)carbamate according to the procedure describedfor Int-B3 step 1.

¹H NMR (400 MHz, DMSO-d₆) δ 7.21 (d, J=8.0 Hz, 1H), 4.70-4.63 (m, 1H),3.65-3.58 (m, 1H), 3.12 (s, 3H), 2.69-2.63 (m, 2H), 2.16-2.09 (m, 2H),1.37 (s, 9H).

Step 3: S-(trans-3-((tert-Butoxycarbonyl)amino)cyclobutyl) Ethanethioate

The title compound was prepared fromcis-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate accordingto the method described for Int-B3 step 2.

¹H NMR (400 MHz, DMSO-d₆) δ 7.29 (d, J=7.6 Hz, 1H), 4.11-4.04 (m, 1H),3.84-3.79 (m, 1H), 2.46-2.39 (m, 2H), 2.29 (s, 3H), 2.18-2.12 (m, 2H),1.37 (s, 9H).

Int-B10: S-(4-((tert-Butoxycarbonyl)amino)cycloheptyl) Ethanethioate

Step 1: tert-Butyl (4-oxocycloheptyl)carbamate

The title compound was prepared from tert-butyl(4-oxocyclohexyl)carbamate according to the procedure described in Liu,H.; et al, Chem. Eur. J 2012, 18, 11889: To a solution of n-BuLi (2 M inhexane, 9.76 mL, 24.4 mmol, 1.3 eq) in Et₂O (50 mL) at −78° C. under aN₂ atmosphere was added TMSCH₂N₂ (12 mL, 24.4 mmol, 1.3 eq) dropwise andthe mixture was allowed to stir at −78° C. for 30 min. A solution oftert-butyl (4-oxocyclohexyl)carbamate (4.0 g, 18.8 mmol, 1.0 eq) in Et₂O(50 mL) was then added dropwise and the solution was stirred at −78° C.for a further 30 min. The reaction was quenched with MeOH (1.6 mL) andallowed to warm to RT, diluted with water (50 mL) and extracted withEt₂O (50 mL). The combined organic layers were washed with brine (50mL), dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (Petroleum ether:EtOAc,8:1 to 6:1, v/v) to afford the title compound as a 2:1 mixture ofisomers (1.8 g, 42%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 2.59-2.46 (m, 1H), 2.33-2.12 (m, 4H),2.01-1.68 (m, 4H), 1.43 (s, 9H), 1.25-1.06 (m, 2H).

Step 2: S-(4-((tert-Butoxycarbonyl)amino)cycloheptyl) Ethanethioate

The title compound was prepared from tert-butyl(4-oxocycloheptyl)carbamate according to the methods described forInt-B7 and obtained as a 2:1 mixture of isomers.

¹HNMR (400 MHz, CDCl₃) δ 3.69-3.52 (m, 2H), 2.32 (s, 1H), 2.04 (s, 2H),2.12-1.85 (m, 4H), 1.85-1.54 (m, 6H), 1.43 (s, 9H).

Int-B11: trans-4-Mercaptocyclohexanol

To a solution 7-oxabicyclo[2.2.1]heptane (1 g, 10.2 mmol, 1.0 eq) inethanol (10 mL) was added p-TSA (2.91 g, 15.3 mmol) and thiourea (1.2 g,15.8 mmol, 1.5 eq) and the mixture was heated at reflux for 21 h. Aftercooling to RT, NaOH (1.3 g) and water (3 mL) were added and the solutionwas heated at reflux for a further 2 h. The mixture was cooled to RT,NaOH (1.3 g) and water (3 mL) were added and the solution was heated atreflux for a further 2 h, then allowed to cool to RT and concentratedunder reduced pressure. The residue was diluted with water (15 mL) andadjusted to pH 3-4 with 1 M HCl and extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (Petroleum ether:EtOAc, 10:1, v/v) to affordthe title compound (500 mg, 37%) as a yellow oil.

¹HNMR (400 MHz, DMSO-d₆) δ 6.18 (br s, 1H), 4.51 (br s, 1H), 3.41-3.36(m, 1H), 2.73-2.64 (m, 1H), 1.96-1.86 (m, 2H), 1.72-1.81 (m, 2H),1.36-1.26 (m, 2H), 1.23-1.17 (m, 2H).

Int-B12: S-(4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)Ethanethioate

Step 1: 4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexylMethanesulfonate

The title compound was prepared from ethyl4-hydroxycyclohexanecarboxylate (54.3 g, 300 mmol) according to theprocedure described in US2005/0054658 yielding a 1:1 mixture ofcis/trans isomers (91.0 g, 94%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 5.04-4.94 (m, 1H), 4.64-4.52 (m, 1H), 3.44 (d,J=6.4 Hz, 2H), 3.40 (d, J=6.4 Hz, 2H), 3.01 (s, 3H), 3.00 (s, 3H),2.21-2.15 (m, 2H), 2.10-2.06 (m, 2H), 1.90-1.83 (m, 2H), 1.69-1.50 (m,6H), 1.40-1.33 (m, 4H), 1.12-1.01 (m, 2H), 0.89 (s, 9H), 0.88 (s, 9H),0.04 (s, 6H), 0.03 (s, 6H).

Step 2: S-(4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)Ethanethioate

The title compound was prepared from4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl methanesulfonateaccording to the procedure described for Int-B3 step 2.

Ratio of cis/trans isomers=1:2

¹H NMR (400 MHz, CDCl₃) δ 3.49-3.45 (m, 1H), 3.42-3.38 (m, 2H), 2.30 (s,2H), 2.29 (s, 1H), 2.12-1.11 (m, 9H), 0.89 (s, 6H), 0.88 (s, 3H), 0.04(s, 4H), 0.03 (s, 2H).

Int-B13: S-(3-(Hydroxymethyl)cyclohexyl) Ethanethioate

Step 1: Ethyl 3-((methylsulfonyl)oxy)cyclohexanecarboxylate

The title compound was prepared from ethyl3-hydroxycyclohexanecarboxylate according to the procedure described forInt-B3 step 1.

Ratio of cis/trans isomers=2:3

¹H NMR (400 MHz, CDCl₃) δ 5.05 (m, 0.4H), 4.66-4.59 (m, 0.6H), 4.14 (q,J=6.8 Hz, 2H), 3.01 (s, 3H), 2.39-2.37 (m, 1H), 2.16-2.14 (m, 1H),1.94-1.87 (m, 2H), 1.73-1.32 (m, 5H), 1.25 (t, J=6.4 Hz, 3H).

Step 2: 3-(Hydroxymethyl)cyclohexyl Methanesulfonate

To a solution of ethyl 3-((methylsulfonyl)oxy)cyclohexanecarboxylate(7.2 g, 28.8 mmol, 1.0 eq) in DME (20 mL) at 0° C. was added a solutionof LiBH₄ in THF (14.4 mL, 2 M, 28.8 mmol, 1.0 eq) and the mixture wasallowed to warm to RT and stirred overnight. The mixture wasconcentrated under reduced pressure, diluted with water (80 mL) andextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄ and concentrated under reducedpressure to afford the title compound (4.7 g, 78%) as a colorless oil,which was used for the next step without further purification.

Ratio of cis/trans isomers=3:7

¹H NMR (400 MHz, CDCl₃) δ 5.05 (m, 0.3H), 4.64-4.59 (m, 0.7H), 3.52-3.44(m, 2H), 2.99 (s, 3H), 2.23-1.85 (m, 4H), 1.78-1.21 (m, 5H).

Step 3: S-(3-(Hydroxymethyl)cyclohexyl) Ethanethioate

The title compound was prepared from 3-(hydroxymethyl)cyclohexylMethanesulfonate according to the procedure described for Int-B3 step 2.

¹H NMR (400 MHz, CDCl₃) δ 3.98-3.95 (m, 1H), 3.53-3.45 (m, 2H), 2.30 (s,3H), 1.86-1.46 (m, 9H).

Intermediate C1: ((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)Ethanethioate

To a solution of Int A1 (5.0 g, 24 mmol, 1 eq) in DMF (50 mL) at RTunder a N₂ atmosphere was added AcSH (3.7 g, 48 mmol, 2 eq) and themixture was heated at 80° C. for 16 h. After cooling to RT, the mixturewas diluted with petroleum ether and the resulting precipitate wascollected by filtration and dried to give the title product (6 g, 100%)as a yellow solid, which was used in the subsequent steps withoutfurther purification. LCMS: [M+H]⁺ 249.1.

The following intermediates in Table 2 were similarly prepared from theappropriate intermediate A precursor and AcSH according to the methoddescribed for Intermediate C1.

TABLE 2 Int. A LCMS: Intermediate Name Precursor [M + H]⁺

S-((6-methyl-4-oxo-3,4- dihydroquinazolin-2- yl)methyl) ethanethioate A3249.1

S-((6-methoxy-4-oxo-3,4- dihydroquinazolin-2- yl)methyl) ethanethioateA6 265.1

S-((8-benzyl-4-oxo-3,4- dihydroquinazolin-2- yl)methyl) ethanethioateA35 325.1

S-(1-(8-methyl-4-oxo-3,4- dihydroquinazolin-2-yl)ethyl) ethanethioateA33 263.1

S-((5-fluoro-8-methyl-4-oxo- 3,4-dihydroquinazolin-2- yl)methyl)ethanethioate A21 267.1

S-((7-cyano-4-oxo-3,4- dihydroquinazolin-2- yl)methyl) ethanethioate A18260.0

S-((5-methyl-4-oxo-3,4- dihydroquinazolin-2- yl)methyl) ethanethioateA15 249.1

Int-C9: S-((8-Chloro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)Ethanethioate

To a solution of Int-A7 (530 mg, 2.3 mmol, 1 eq) in THF (15 mL) and EtOH(5 mL) at RT under a N₂ atmosphere was added AcSH (266 mg, 3.5 mmol, 1.5eq) and the mixture was heated at 70° C. for 3 h. After cooling to RT,the mixture was concentrated under reduced pressure. The residue waspurified by column chromatography (Petroleum ether:EtOAc, 15:1, v/v) toafford the title compound (300 mg, 48%) as a white solid. LCMS: [M+H]⁺269.0.

Int-C10: S-((8-Methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)Ethanethioate

The title compound was prepared from Int-A4 according to the proceduredescribed for Int-C9. LCMS: [M+H]⁺ 265.1.

Int-C11: S-((7-Benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)Ethanethioate

To a suspension of Int A36 (27 mg, 0.1 mmol, 1 eq) and NaHCO₃(10 mg,0.11 mmol, 1.1 eq) in DMF (3 mL) at RT under a N₂ atmosphere was addedAcSH (8 mg, 0.12 mmol, 1.2 eq) and the mixture was stirred at RTovernight. The mixture was diluted with water (4 mL) and the resultingprecipitate was collected by filtration and dried to give the titleproduct (20 mg, 70%) as a white solid. LCMS: [M+H]⁺ 325.1.

Example Compounds Example 1:4-Oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carbonitrile

To a solution of Int-C7 (60 mg, 0.23 mmol, 1 eq) and4-bromotetrahydro-2H-pyran (38 mg, 0.23 mmol, 1.0 e1) in DMF (2 mL) atRT under a N₂ atmosphere was added 1 M NaOH (0.5 mL) and the mixture washeated at 90° C. for 16 h. The mixture was poured into water (5 mL),extracted with EtOAc (10 mL×3) and the combined organic layers werewashed with water (10 mL), dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography(Petroleum ether:EtOAc, 15:1, v/v) to afford the title compound (15 mg,22%) as a colorless oil. LCMS: [M+H]⁺ 302.1.

¹H NMR (400 MHz, CD₃OD) δ 8.32 (d, J=8.0 Hz, 1H), 8.03 (s, 1H), 7.78(dd, J=8.0, 1.6 Hz, 1H), 3.91 (dt, J=11.6, 3.6 Hz, 2H), 3.75 (s, 2H),3.43 (td, J=11.6, 2.3 Hz, 2H), 3.09-3.01 (m, 1H), 2.02-1.90 (m, 2H),1.63-1.53 (m, 2H).

The following examples in Table 3 were similarly prepared from theappropriate intermediate C and 4-bromotetrahydro-2H-pyran according tothe method described for Example 1.

TABLE 3 Example Name and structure Int. Example 2

C1 Example 3

C2 Example 4

C3 Example 5

C9 Example 6

C10 Example 7

C5 Example 8

C6 Example 9

C8 Example 10

C4 Example 11

C11

Example 12:8-Methyl-2-((((tetrahydro-2H-pyran-4-yl)methyl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from Int-C1 and4-(bromomethyl)tetrahydro-2H-pyran according to the method described forExample 1. LCMS: [M+H]⁺ 305.1.

¹H NMR (400 MHz, CDCl₃) δ 10.2 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.62 (d,J=7.2 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 4.00-3.90 (m, 2H), 3.74 (d, J=2.8Hz, 2H), 3.33 (td, J=11.6, 2.0 Hz, 2H), 2.60 (d, J=2.8 Hz, 3H), 2.48 (d,J=6.8 Hz, 2H), 1.78-1.69 (m, 3H), 1.35-1.24 (m, 2H).

Example 13: 8-Methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneTrifluoroacetate

Step 1: tert-Butyl4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

To a solution of Int-C1 (6.6 g, 26.6 mmol, 1.0 eq) and tert-butyl4-bromopiperidine-1-carboxylate (7.0 g, 26.6 mmol, 1.0 eq) in DMF (130mL) at RT under a N₂ atmosphere was added 1 M NaOH (50 mL) and themixture was heated at 80° C. for 16 h. The mixture was poured into water(50 mL), extracted with EtOAc (100 mL×3) and the combined organic layerswere dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (Petroleum ether:EtOAc,4:1, v/v) to afford the title compound (7.2 g, 70%) as a light yellowsolid. LCMS: [M+H]⁺ 390.2.

Step 2: 8-Methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneTrifluoroacetate

tert-Butyl4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate(30 mg, 0.08 mmol, 1.0 eq) was dissolved in TFA (5 mL) and the mixturewas stirred at RT for 5 h. The mixture was concentrated under reducedpressure to give the title product (20 mg, 45%) as a yellow solid. LCMS:[M+H]⁺ 290.2.

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=8.0 Hz, 1H), 7.75-7.60 (m, 1H),7.39 (t, J=7.6 Hz, 1H), 3.80 (s, 2H), 3.42-3.36 (m, 2H), 3.26-3.12 (m,1H), 3.09-2.97 (m, 2H), 2.59 (s, 3H), 2.32-2.28 (m, 2H), 1.83-1.74 (m,2H).

Example 14:8-Methyl-2-(((1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of Example 13 (160 mg, 0.37 mmol, 1.0 eq) and formaldehyde(30% in water, 0.34 mL, 3.7 mmol, 10.0 eq) in MeOH (10 mL) was addedAcOH (67 mg, 1.1 mmol, 3.0 eq) and NaCNBH₃ (93 mg, 1.5 mmol, 4.0 eq) andthe mixture was stirred at RT overnight. The mixture was diluted withwater (30 mL), extracted with DCM (30 mL×3) and the combined organiclayers were washed with water (20 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (DCM:MeOH, 10:1, v/v) to afford the title compound (50mg, 30%) as a light yellow solid. LCMS: [M+H]⁺ 304.2;

¹H NMR (400 MHz, CD₃OD) δ 7.94 (d, J=8.0 Hz, 1H), 7.58 (d, J=7.2 Hz,1H), 7.30 (t, J=7.6 Hz, 1H), 3.74 (s, 2H), 3.28-3.25 (m, 2H), 3.02 (brs, 1H), 2.79 (t, J=11.8 Hz, 2H), 2.60 (s, 3H), 2.50 (s, 3H), 2.25-2.21(m, 2H), 1.80-1.72 (m, 2H).

Example 15: 8-Methyl-2-((pyrrolidin-3-ylthio)methyl)quinazolin-4(3H)-oneTrifluoroacetate

The title compound was prepared from Int-C1 and tert-butyl3-bromopyrrolidine-1-carboxylate according to the method described forExample 13. LCMS: [M+H]⁺ 276.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.4 (s, 1H), 9.00 (s, 2H), 7.94 (d, J=7.8Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.38 (t, J=7.4 Hz, 1H), 3.75 (s, 2H),3.65 (dt, J=12.8, 6.8 Hz, 1H), 3.59-3.49 (m, 1H), 3.31-3.15 (m, 2H),3.14-3.04 (m, 1H), 2.52 (s, 3H), 2.36-2.35 (m, 1H), 1.90-1.78 (m, 1H).

Example 16:8-Methyl-2-(((1-methylpyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from Example 15 according to the methoddescribed for Example 14. LCMS: [M+H]⁺ 290.1.

¹H NMR (400 MHz, DMSO-d₆) δ 12.3 (br s, 1H), 7.92 (d, J=7.6 Hz, 1H),7.65 (d, J=7.2 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 3.65 (s, 2H), 3.48-3.38(m, 1H), 2.87-2.77 (m, 1H), 2.50 (s, 3H), 2.43 (dd, J=13.2, 6.4 Hz, 2H),2.28 (dd, J=9.6, 5.6 Hz, 1H), 2.22-2.11 (m, 4H), 1.56 (td, J=13.2, 6.4Hz, 1H).

Example 17:2-(((1-Acetylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

To a solution of Example 13 (20 mg, 0.07 mmol, 1.0 eq) and Et₃N (14 mg,0.14 mmol, 2.0 eq) in DCM (10 mL) at 0° C. was added Ac₂O (8 mg, 0.11mmol, 1.5 eq) dropwise and the mixture was allowed to warm to RT andstirred overnight. The mixture was diluted with DCM (30 mL) and washedwith water (30 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (DCM:MeOH, 20:1, v/v) to afford the title compound (10mg, 43%) as a light yellow solid. LCMS: [M+H]⁺ 332.1.

¹H NMR (400 MHz, CD₃OD) δ 8.04 (d, J=8.0 Hz, 1H), 7.67 (d, J=7.2 Hz,1H), 7.39 (t, J=7.6 Hz, 1H), 4.28 (d, J=13.6 Hz, 1H), 3.86 (d, J=14.0Hz, 1H), 3.78 (s, 2H), 3.23-3.06 (m, 2H), 2.59 (s, 3H), 2.87 (t, J=12.4Hz, 1H), 2.12-2.04 (m, 5H), 1.62-1.41 (m, 2H).

Example 18:8-Methyl-2-(((1-(pyridin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from the compound of Example 13 andpicolinaldehyde according to the method described for Example 14. LCMS:[M+H]⁺ 381.2.

¹H NMR (400 MHz, CD₃OD) δ 8.69 (d, J=4.4 Hz, 1H), 8.05 (d, J=7.6 Hz,1H), 7.91 (td, J=7.6, 1.6 Hz, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.51-7.38 (m,3H), 4.47 (s, 2H), 3.83 (s, 2H), 3.62-3.53 (m, 2H), 3.21 (t, J=11.6 Hz,3H), 2.60 (s, 3H), 2.43-2.31 (m, 2H), 2.08-1.91 (m, 2H).

Example 19:8-Methyl-2-(((tetrahydro-2H-pyran-4-yl)sulfonyl)methyl)quinazolin-4(3H)-one

To a solution of Example 2 (50 mg, 0.17 mmol, 1.0 eq) in AcOH (2 mL) at0° C. was added H₂O₂ (30% solution in water, 195 mg, 1.7 mmol, 10.0 eq)dropwise and the mixture was allowed to warm to RT and stirredovernight. The mixture was diluted with MeOH (2 mL) and purified bycolumn chromatography (DCM:MeOH, 20:1, v/v) to afford the title compound(6 mg, 11%) as a white solid. LCMS: [M+H]⁺ 323.1.

¹H NMR (400 MHz, DMSO-d₆) δ 12.5 (br s, 1H), 7.97 (d, J=8.0 Hz, 1H),7.72 (d, J=7.2 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 4.55 (s, 2H), 4.02 (dd,J=11.2, 4.0 Hz, 2H), 3.95-3.86 (m, 1H), 3.37 (t, J=10.4 Hz, 2H), 2.54(s, 3H), 2.13-2.05 (m, 2H), 1.76-1.65 (m, 2H).

Example 20: 2-((Azepan-4-ylthio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate

Step 1: tert-Butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate

The title compound was prepared from tert-butyl4-hydroxyazepane-1-carboxylate according to the method described forInt-B3, step 1. LCMS: [M+H−56]⁺ 238.1.

Step 2: tert-Butyl4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)azepane-1-carboxylate

To a solution of Int-C1 (615 mg, 2.5 mmol, 1 eq) and tert-butyl4-((methylsulfonyl)oxy)azepane-1-carboxylate (800 mg, 2.7 mmol, 1.1 eq)in DMF (20 mL) at RT under a N₂ atmosphere was added 1 M NaOH (5 mL) andthe mixture was heated at 80° C. for 6 h. The mixture was poured intowater (5 mL), extracted with EtOAc (10 mL×3) and the combined organiclayers were washed with water (10 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (Petroleum ether:EtOAc, 5:1, v/v) to afford the titlecompound (140 mg, 14%) as a white solid. LCMS: [M+H]⁺ 404.2.

Step 3: 2-((Azepan-4-ylthio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate

tert-Butyl4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)azepane-1-carboxylate(140 mg, 0.34 mmol, 1.0 eq) was dissolved in a 3 M HCl/dioxane solution(3 mL) and the mixture was stirred at RT for 3 h. The mixture wasconcentrated under reduced pressure, diluted with water (10 mL) andadjusted pH to 9-10 with a saturated aqueous Na₂CO₃ solution, thenextracted with EtOAc (10 mL×3). The combined organic layers were washedwith water (10 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by C18 reverse phase chromatography(Biotage, 30%-70% ACN in water, 0.1% TFA) to afford the title compound(50 mg, 35%) as a white solid. LCMS: [M+H]⁺ 304.1;

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=8.0 Hz, 1H), 7.67 (d, J=7.2 Hz,1H), 7.39 (t, J=7.6 Hz, 1H), 3.79 (s, 2H), 3.41-3.34 (m, 1H), 3.24-3.11(m, 4H), 2.59 (s, 3H), 2.41-2.30 (m, 1H), 2.27-2.17 (m, 1H), 2.06-1.94(m, 2H), 1.87-1.70 (m, 2H).

Example 21:2-(((4-(Dimethylamino)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

Step 1: 1,4-Dioxaspiro[4,5]decan-8-yl Methanesulfonate

The title compound was prepared from 1,4-dioxaspiro[4.5]decan-8-olaccording to the method described for Int-B3, step 1. ¹H NMR (400 MHz,CDCl₃) δ 4.85-4.80 (m, 1H), 3.97-3.90 (m, 4H), 3.00 (s, 3H), 2.01-1.96(m, 4H), 1.87-1.78 (m, 2H), 1.66-1.60 (m, 2H).

Step 2:2-(((1,4-Dioxaspiro[4.5]decan-8-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

The title compound was prepared from 1,4-dioxaspiro[4.5]decan-8-ylMethanesulfonate and Int-C1 according to the method described forExample 20, step 2. LCMS: [M+H]⁺ 347.1.

Step 3: 8-Methyl-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-one

To a solution of2-(((1,4-dioxaspiro[4.5]decan-8-yl)thio)methyl)-8-methylquinazolin-4(3H)-one(500 mg, 1.4 mmol, 1.0 eq) in THF (20 mL) was added 1 M HCl (20 mL) andthe mixture was stirred at RT overnight. The mixture was diluted withwater (20 mL), extracted with DCM (20 mL×3) and the combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure toafford the title compound (510 mg, 100%) as a yellow solid, which wasused in the subsequent step without further purification. LCMS: [M+H]⁺303.1.

Step 4:2-(((4-(Dimethylamino)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

To a solution of8-methyl-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-one (68 mg,0.22 mmol, 1.0 eq) in THF (3 mL) was added Me₂NH (2 M solution in THF,2.2 mL, 20.0 eq) and NaBH(OAc)₃ (950 mg, 4.5 mmol, 20.0 eq) and themixture was stirred at RT overnight. The mixture was diluted with asaturated aqueous NaHCO₃ solution (20 mL), extracted with EtOAc (30mL×3) and the combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-TLC (DCM:MeOH, 10:1, v/v) to afford the title compound (40 mg, 55%)as a light yellow solid. LCMS: [M+H]⁺ 332.2;

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.2 Hz,1H), 7.38 (t, J=7.6 Hz, 1H), 3.75 (d, J=14.0 Hz, 2H), 3.36 (s, 1H),3.08-2.98 (m, 1H), 2.74 (s, 3H), 2.70 (s, 3H), 2.59 (d, J=9.5 Hz, 3H),2.32-2.25 (m, 1H), 2.11-2.05 (m, 2H), 1.90-1.84 (m, 3H), 1.53-1.37 (m,2H).

Example 22:2-(((4-Hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

To a solution of8-methyl-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-one (preparedin Example 21, Step 4) (100 mg, 0.33 mmol, 1.0 eq) in MeOH (10 mL) wasadded NaBH₄ (25 mg, 0.66 mmol, 2.0 eq) and the mixture was stirred at RTovernight. The mixture was diluted with water (20 mL), extracted withEtOAc (30 mL×3) and the combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified byprep-TLC (DCM:MeOH, 10:1, v/v) to afford the title compound as a 3:2mixture of trans/cis isomers (50 mg, 50%) as a white solid. LCMS: [M+H]⁺305.1.

Example 23:2-((((trans)-4-Hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneAnd Example 24:2-((((cis)-4-Hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

The compound of Example 22 was further purified by prep-HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, eluting with a gradient of MeOH inwater with 0.1% TFA, at a flow rate of 20 mL/min) to afford the titlecompounds.

Example 23

LCMS: [M+H]⁺ 305.1;

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.2 Hz,1H), 7.38 (t, J=8.0 Hz, 1H), 3.72 (s, 2H), 3.52 (t, J=11.2 Hz, 1H), 2.75(t, J=11.6 Hz, 1H), 2.59 (s, 3H), 2.11 (d, J=12.8 Hz, 2H), 1.95 (d,J=12.4 Hz, 2H), 1.44-1.15 (m, 4H).

Example 24

LCMS: [M+H]⁺ 305.1;

¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, J=8.0 Hz, 1H), 7.65 (d, J=7.2 Hz,1H), 7.37 (t, J=8.0 Hz, 1H), 3.72 (s, 3H), 2.99 (t, J=6.0 Hz, 1H), 2.58(s, 3H), 1.82-1.70 (m, 6H), 1.64-1.49 (m, 2H).

Example 25: 2-((Azetidin-3-ylthio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate

Step 1: tert-Butyl3-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)azetidine-1-carboxylate

The title compound was prepared from Int-C1 and tert-butyl3-iodoazetidine-1-carboxylate according to the method described forExample 13, step 1. LCMS: [M+H]⁺ 362.2.

Step 2: 2-((Azetidin-3-ylthio)methyl)-8-methylquinazolin-4(3H)-oneHydrochloride

tert-Butyl3-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)azetidine-1-carboxylate(40 mg, 0.11 mmol, 1.0 eq) was dissolved in a 1.5 M HCl/EtOAc solution(3 mL) and the mixture was stirred at RT overnight. The mixture wasdiluted with water (10 mL), adjusted to pH 9-10 with a saturated aqueousNa₂CO₃ solution and extracted with EtOAc (10 mL×3). The combined organiclayers were washed with water (10 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2 mm column, eluting witha gradient of MeOH in water with 0.1% TFA, at a flow rate of 20 mL/min)to afford the title compound (1.8 mg, 6%) as a white solid. LCMS: [M+H]⁺262.1.

¹H NMR (400 MHz, CD₃OD) δ 8.04 (d, J=8.0 Hz, 1H), 7.68 (d, J=7.2 Hz,1H), 7.41 (t, J=7.6 Hz, 1H), 4.35 (t, J=9.6 Hz, 2H), 4.27-4.21 (m, 1H),3.89 (t, J=9.2 Hz, 2H), 3.81 (s, 2H), 2.62 (s, 3H); ¹⁹F NMR (400 MHz,CD₃OD) δ −78.2.

Example 26:2-((((trans)-4-Methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneand Example 27:2-((((cis)-4-Methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

Step 1: 4-Methoxycyclohexyl Methanesulfonate

The title compound was prepared from 4-methoxycyclohexanol according tothe method described for Int-B3, Step 1.

¹H NMR (400 MHz, CDCl₃) δ 4.80-4.70 (m, 1H), 3.32 (s, 3H), 3.30-3.25 (m,1H), 3.01 (s, 3H), 2.12-2.05 (m, 1H), 2.04-1.93 (m, 2H), 1.86-1.65 (m,4H), 1.55-1.45 (m, 1H).

Step 2:2-(((4-Methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

The title compound was prepared from 4-methoxycyclohexylMethanesulfonate and Int-C1 according to the method described forExample 20, Step 2. LCMS: [M+H]⁺ 319.1.

Step 3:2-(((trans-4-Methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneand2-(((cis-4-Methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

2-(((4-Methoxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one waspurified by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2 mm column,eluting with a gradient of MeOH in water with 0.1% TFA, at a flow rateof 20 mL/min) to afford the title compounds.

Example 26

LCMS: [M+H]⁺ 319.1;

¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=8.0 Hz, 1H), 7.61 (d, J=7.2 Hz,1H), 7.37 (t, J=7.6 Hz, 1H), 3.79 (s, 2H), 3.31 (s, 3H), 3.17-3.10 (m,1H), 2.64-2.71 (m, 1H), 2.59 (s, 3H), 2.14-1.99 (m, 4H), 1.44-1.30 (m,2H), 1.27-1.17 (m, 2H).

Example 27

LCMS: [M+H]⁺ 319.1;

¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.2 Hz,1H), 7.31 (t, J=7.6 Hz, 1H), 3.78 (s, 2H), 3.29-3.23 (m, 1H), 3.22 (s,3H), 2.72-2.66 (m, 1H), 2.55 (s, 3H), 1.88-1.76 (m, 2H), 1.72-1.64 (m,4H), 1.46-1.36 (m, 2H).

Example 28:4-Oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-8-carbonitrile

To a solution of Int-A17 (36 mg, 0.16 mmol, 1.0 eq) and Int-B1 (26 mg,0.16 mmol, 1.0 eq) in DMF (2 mL) was added 1 M NaOH (2 mL) and themixture was stirred at RT overnight under a N₂ atmosphere. The mixturewas diluted with water (5 mL) and extracted with EtOAc (20 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by prep-TLC (Petroleumether:EtOAc, 1:1, v/v) to afford the title compound (12 mg, 24%) as awhite solid. LCMS: [M+H]⁺ 302.1;

¹H NMR (400 MHz, CDCl₃) δ 10.4 (s, 1H), 8.48 (d, J=8.0 Hz, 1H), 8.10 (d,J=7.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 3.97 (dd, J=12.0, 3.6 Hz, 2H),3.87 (s, 2H), 3.42 (t, J=11.2 Hz, 2H), 2.99 (td, J=10.8, 5.2 Hz, 1H),1.96 (d, J=12.8 Hz, 2H), 1.72-1.62 (m, 2H).

The following Examples in Table 4 were similarly prepared from theappropriate intermediate A and intermediate B according to the methoddescribed for Example 28.

TABLE 4 Example Name and structure Intermediates Example 29

A19, B1 Example 30

A9, B1 Example 31

A5, B1 Example 32

A1, B3 Example 33

A23, B1 Example 34

A22, B1 Example 35

A20, B1 Example 36

A27, B1 Example 37

A28, B1 Example 38

A1, B7 Example 39

A1, B8 Example 40

A31, B1 Example 41

A30, B1 Example 42

A29, B1 Example 43

A32, B1 Example 44

A13, B1 Example 45

A25, B1

Example 46:7-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

To a solution of Int-A9 (200 mg, 0.94 mmol, 1.0 eq) and Int-B11 (249 mg,1.13 mmol) in DMF (5 mL) was added 1 M NaOH (3 mL) and the mixture wasstirred at RT overnight under a N₂ atmosphere. The mixture was dilutedwith water (50 mL) and extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with water (100 mL) and brine (100 mL), driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by prep-TLC (100% EtOAc) to afford the title compound (260 mg,90%) as a white solid. LCMS: [M+H]⁺ 309.1.

¹H NMR (400 MHz, DMSO-d₆) δ 12.4 (s, 1H), 8.15 (dd, J=6.4, 8.8 Hz, 1H),7.42-7.34 (m, 2H), 4.52 (d, J=4.4 Hz, 1H), 3.63 (s, 2H), 3.41-3.32 (m,1H), 2.78-2.68 (m, 1H), 2.01-1.92 (m, 2H), 1.85-1.76 (m, 2H), 1.29-1.10(m, 4H).

Example 47:2-(((trans-3-Hydroxycyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-one

To a solution of Example 38 (100 mg, 0.27 mmol, 1.0 eq) in DCM (5 mL)was added N,N-dimethylaniline (2 mg, catalytic) and AlCl₃ (364 mg, 2.7mmol, 10.0 eq) and the mixture was stirred at RT for 2 h. The mixturewas diluted with water (20 mL), adjusted pH to 3-4 with 1 M HCl andextracted with EtOAc (20 mL×3). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. The residue waswashed with hexane (5 mL) to afford the title compound (40 mg, 53%) as ayellow solid. LCMS: [M+H]⁺ 277.1.

¹H NMR (400 MHz, DMSO-d₆) δ 12.3 (s, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.66(d, J=7.2 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 4.29 (p, J=6.6 Hz, 1H), 3.60(s, 2H), 3.54-3.47 (m, 1H), 3.30 (1H (OH) may be obscured by waterpeak), 2.52 (s, 3H), 2.25-2.15 (m, 2H), 2.13-2.07 (m, 2H).

Example 48: 8-Methyl-2-((piperidin-3-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Step 1: tert-Butyl3-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

The title compound was prepared from Int-A1 and Int-B4 according to themethod described for Example 28. LCMS: [M+H]⁺ 362.2.

Step 2: 8-Methyl-2-((piperidin-3-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

tert-Butyl3-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate(120 mg, 0.31 mmol, 1.0 eq) was dissolved in a 1.5 M HCl/EtOAc solution(10 mL) and the mixture was stirred at RT for 3 h. The mixture wasconcentrated under reduced pressure to afford the title compound (70 mg,79%) as a white solid. LCMS: [M+H]⁺ 290.1.

¹H NMR (400 MHz, DMSO-d₆) δ 12.4 (br s, 1H), 9.27-9.14 (m, 2H), 7.93 (d,J=7.6 Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 3.87-3.72(m, 2H), 3.52-3.45 (m, 1H), 3.29-3.18 (m, 1H), 3.18-3.09 (m, 1H),2.89-2.78 (m, 2H), 2.55 (s, 3H), 2.04 (dd, J=18.4, 7.6 Hz, 1H),1.85-1.63 (m, 2H), 1.56-1.41 (m, 1H).

Example 49:2-(((trans-4-Aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneHydrochloride

The title compound was prepared from Int-A1 and Int-B5-trans accordingto the method described for Example 48. LCMS: [M+H]⁺ 304.1.

¹H NMR (400 MHz, DMSO-d₆) δ 12.3 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.76(br s, 3H), 7.66 (d, J=7.2 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 3.65 (s,2H), 3.29-3.25 (m, 1H), 3.05 (br s, 1H), 2.5 (s, 3H), 1.90-1.57 (m, 8H).

Example 50:2-(((cis-4-Aminocyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetic Acid

The title compound was prepared from Int-A1 and Int-B5-cis according tothe method described for Example 48. LCMS: [M+H]⁺ 304.1.

¹H NMR (400 MHz, DMSO-d₆) δ 12.3 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.75(s, 3H), 7.66 (d, J=7.2 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 3.65 (s, 2H),3.29-3.25 (m, 1H), 3.05 (br s, 1H), 2.50 (s, 3H), 1.90-1.57 (m, 8H).

Example 51:5-Fluoro-8-methyl-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

The title compound was prepared from Int-A21 and Int-B2 according to themethod described for Example 48. LCMS: [M+H]⁺ 308.1.

¹H NMR (400 MHz, DMSO-d₆) δ 12.4 (s, 1H), 9.11-8.83 (m, 2H), 7.64 (t,J=7.2 Hz, 1H), 7.13 (t, J=9.6 Hz, 1H), 3.70 (s, 2H), 3.25-3.11 (m, 3H),2.88 (q, J=11.2 Hz, 2H), 2.43 (s, 3H), 2.15 (d, J=14.0 Hz, 2H),1.73-1.64 (m, 2H).

Example 52:2-(((trans-3-Aminocyclobutyl)thio)methyl)-8-methylquinazolin-4(3H)-oneHydrochloride

The title compound was prepared from Int-A1 and Int-B9 according to themethod described for Example 48. LCMS: [M+H]⁺ 276.1.

¹H NMR (400 MHz, DMSO-d₆) δ 12.3 (br s, 1H), 8.38 (br s, 3H), 7.93 (d,J=7.2 Hz, 1H), 7.66 (d, J=7.1 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 3.82-3.71(m, 2H), 3.69 (s, 2H), 2.53 (s, 5H), 2.21-2.11 (m, 2H).

Example 53:2-(((4-Aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate

The title compound was prepared from Int-A1 and Int-B10 according to themethod described for Example 48. LCMS: [M+H]⁺ 318.2.

Example 54:2-(((trans-4-Aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate and Example 55:2-(((cis-4-Aminocycloheptyl)thio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate

The compound of Example 53 was further purified by prep-HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, eluting with a gradient of ACN inwater with 0.1% TFA, at a flow rate of 20 mL/min) to afford the titlecompounds.

Example 54

LCMS: [M+H]⁺ 318.2.

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.2 Hz,1H), 7.39 (t, J=7.6 Hz, 1H), −3.30 (2H, obscured by solvent peak),3.29-3.22 (m, 1H), 3.09-3.01 (m, 1H), 2.59 (s, 3H), 2.26-2.16 (m, 1H),2.11-2.00 (m, 3H), 1.76-1.49 (m, 6H).

Example 55

LCMS: [M+H]⁺ 318.2.

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.2 Hz,1H), 7.39 (t, J=7.6 Hz, 1H), −3.30 (2H, obscured by solvent peak),3.28-3.20 (m, 1H), 3.17-3.09 (m, 1H), 2.58 (s, 3H), 2.25-2.15 (m, 1H),2.12-2.06 (m, 1H), 2.0-1.93 (m, 2H), 1.92-1.80 (m, 3H), 1.57-1.42 (m,3H).

Example 56:5-Fluoro-2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

Step 1:2-((1,4-Dioxaspiro[4.5]decan-8-ylthio)methyl)-5-fluoro-8-methylquinazolin-4(3H)-one

The title compound was prepared from Int-A21 and Int-B6 according to themethod described for Example 28. LCMS: [M+H]⁺ 365.1.

Step 2:5-Fluoro-8-methyl-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from2-((1,4-dioxaspiro[4.5]decan-8-ylthio)methyl)-5-fluoro-8-methylquinazolin-4(3H)-oneaccording to the method described for Example 21, step 3. LCMS: [M+H]⁺321.1.

Step 3:5-Fluoro-2-(((4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

The title compound was prepared from5-fluoro-8-methyl-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-oneaccording to the procedure described for Example 22. LCMS: [M+H]⁺ 323.1;

Example 57:5-Fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneand Example 58:5-Fluoro-2-(((cis-4-hydroxycyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

The compound of Example 56 was further purified by prep-HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, eluting with a gradient of MeOH inwater with 0.1% TFA, at a flow rate of 20 mL/min) to afford the titlecompounds.

Example 57

LCMS: [M+H]⁺ 323.1.

¹H NMR (400 MHz, CD₃OD) δ 7.62 (dd, J=8.4, 5.6 Hz, 1H), 7.06 (dd,J=11.2, 8.4 Hz, 1H), 3.69 (s, 2H), 3.56-3.49 (m, 1H), 2.80-2.73 (m, 1H),2.52 (s, 3H), 2.16-2.08 (m, 2H), 2.00-1.91 (m, 2H), 1.42-1.33 (m, 2H),1.30-1.20 (m, 2H).

Example 58

LCMS: [M+H]⁺ 323.1.

¹H NMR (400 MHz, CD₃OD) δ 7.61 (dd, J=8.4, 5.6 Hz, 1H), 7.06 (dd,J=11.2, 8.4 Hz, 1H), 3.77-3.72 (m, 1H), 3.69 (s, 2H), 3.00 (m, J=6.0 Hz,1H), 2.51 (s, 3H), 1.83-1.69 (m, 6H), 1.63-1.56 (m, 2H).

Example 59:2-(((4-Hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one

The title compound was prepared from Int-A20 and Int-B6 according to themethod described for Example 56. LCMS: [M+H]⁺ 373.1.

Example 60:2-(((trans-4-Hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one and Example 61:2-(((cis-4-Hydroxycyclohexyl)thio)methyl)-8-methyl-5-(trifluoromethyl)quinazolin-4(3H)-one

The compound of Example 59 was further purified by prep-HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, eluting with a gradient of MeOH inwater with 0.1% TFA, at a flow rate of 20 mL/min) to afford the titlecompounds.

Example 60

LCMS: [M+H]⁺ 373.1.

¹H NMR (400 MHz, CD₃OD) δ 7.78-7.73 (m, 2H), 3.71 (s, 2H), 3.58-3.46 (m,1H), 2.81-2.73 (m, 1H), 2.64 (s, 3H), 2.12 (d, J=12.8 Hz, 2H), 1.96 (d,J=12.8 Hz, 2H), 1.43-1.18 (m, 4H).

Example 61

LCMS: [M+H]⁺ 373.1.

¹H NMR (400 MHz, CD₃OD) δ 7.89-7.58 (m, 2H), 3.77-3.73 (m, 1H), 3.71 (s,2H), 3.04-2.96 (m, 1H), 2.62 (s, 3H), 1.84-1.79 (m, 4H), 1.77-1.69 (m,2H), 1.65-1.53 (m, 2H).

Example 62:2-(((trans-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneand Example 63:2-(((cis-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

Step 1:2-(((4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

The title compound was prepared from Int-A1 and Int-B12 according to themethod described for Example 28. LCMS: [M+H]⁺ 433.2.

Step 2:2-(((trans-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneand2-(((cis-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

To a solution of2-(((4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one(1.2 g, 2.7 mmol, 1.0 eq) in THF (10 mL) was added TBAF (913 mg, 3.5mmol, 1.3 eq) and the mixture was heated at 50° C. for 6 h. The mixturewas allowed to cool to RT, diluted with water (50 mL) and extracted withEtOAc (50 mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (DCM:MeOH, 30:1 to 15:1, v/v) to afford Example 62 (100mg, 12%) and Example 63 (150 mg, 17%) as white solids. Mixed fractionsof Example 62/Example 63 in 1:3 ratio (400 mg, 47%) were also obtained.

Example 62

LCMS: [M+H]⁺ 319.1.

¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=7.6 Hz, 1H), 7.66 (d, J=7.2 Hz,1H), 7.44 (t, J=7.6 Hz, 1H), 4.14 (s, 2H), 3.42 (d, J=6.0 Hz, 2H), 2.71(s, 3H), 2.70-2.59 (m, 1H), 2.11 (d, J=12.8 Hz, 2H), 1.85 (d, J=13.2 Hz,2H), 1.56-1.43 (m, 1H), 1.41-1.25 (m, 2H), 1.06-0.92 (m, 2H).

Example 63

LCMS: [M+H]⁺ 319.1.

¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=7.2 Hz, 1H), 7.65 (d, J=7.2 Hz,1H), 7.42 (t, J=7.6 Hz, 1H), 4.06 (s, 2H), 3.51 (d, J=5.6 Hz, 2H),3.22-3.11 (m, 1H), 2.70 (s, 3H), 1.91-1.80 (m, 2H), 1.79-1.69 (m, 2H),1.61-1.54 (m, 3H), 1.47 (t, J=11.6 Hz, 2H).

Example 64:2-(((4-(Aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate and Example 65:2-(((cis-4-(Aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate

Step 1:(4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methylmethanesulfonate

To a solution of Example 62/Example 63 (1:3 mixture, 400 mg, 1.3 mmol,1.0 eq) and Et₃N (381 mg, 3.8 mmol, 3.0 eq) in DCM (12 mL) at 0° C.under a N₂ atmosphere was added MsCl (288 mg, 2.6 mmol, 2.0 eq) dropwiseand the mixture was allowed to warm to RT and stirred for 3 h. Themixture was diluted with water (20 mL), extracted with DCM (30 mL×3) andthe combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure to afford the title compound (498 mg, 100%) asyellow solid. LCMS: [M+H]⁺ 397.1

Step 2:2-(((4-(Azidomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

To a solution of(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methylmethanesulfonate (350 mg, 0.88 mmol, 1.0 eq) in DMF (8 mL) under a N₂atmosphere was added NaN₃ (172 mg, 2.6 mmol, 3.0 eq) and the mixture washeated at 50° C. for 5 h. The mixture was cooled to RT, diluted withwater (20 mL) and extracted with DCM (30 mL×3). The combined organiclayers were washed with water (20 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (Petroleum ether:EtOAc, 10:1 to 5:1, v/v) to afford thetitle compound (200 mg, 75%) as yellow solid. LCMS: [M+H]⁺ 344.2.

Step 3:2-(((4-(Aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate and2-(((cis-4-(Aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate

To a solution of2-(((4-(azidomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one(190 mg, 0.54 mmol, 1.0 eq) in THF (8 mL) and water (0.1 mL) under a N₂atmosphere was added PPh₃ (217 mg, 0.84 mmol, 1.5 eq) and the mixturewas stirred at RT for 24 h. The mixture was concentrated under reducedpressure and the residue was purified by prep-HPLC (Agilent 10 prep-C18,10 μm, 250×21.2 mm column, eluting with a gradient of ACN in water with0.1% TFA, at a flow rate of 20 mL/min) to afford Example 64 (45.8 mg,26%) and Example 65 (45.1 mg, 26%) as white solids.

Example 64

LCMS: [M+H]⁺ 318.2;

Example 65

LCMS: [M+H]⁺ 318.2; ¹H NMR (400 MHz, DMSO-d₆) δ 12.3 (s, 1H), 7.94 (d,J=7.6 Hz, 1H), 7.67 (d, J=7.6 Hz, 4H), 7.38 (t, J=7.6 Hz, 1H), 3.64 (s,2H), 3.28-3.24 (m, 1H), 2.71 (t, J=5.2 Hz, 2H), 2.50 (s, 3H), 1.82-1.67(m, 4H), 1.65-1.60 (m, 1H), 1.55-1.50 (m, 2H), 1.39-1.30 (m, 2H).

Example 66:2-(((trans-4-(Aminomethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate

The compound of Example 64 was further purified by prep-HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, eluting with a gradient of ACN inwater with 0.1% TFA, at a flow rate of 15 mL/min) to afford the titlecompound. LCMS: [M+H]⁺ 318.2.

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=7.2 Hz, 1H), 7.65 (d, J=7.2 Hz,1H), 7.38 (t, J=7.6 Hz, 1H), 3.75 (s, 2H), 2.78-2.70 (m, 3H), 2.58 (s,3H), 2.25-2.08 (m, 2H), 1.92-1.78 (m, 2H), 1.66-1.55 (m, 1H), 1.34 (qd,J=12.8, 3.2 Hz, 2H), 1.05 (qd, J=12.8, 3.2 Hz, 2H).

Example 67:2-(((4-((Dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate and Example 68:2-(((cis-4-((Dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one Trifluoroacetate

A mixture of(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methylmethanesulfonate (200 mg, 0.5 mmol, 1.0 eq), Et₃N (101 mg, 1 mmol, 2.0eq) and dimethylamine (2 M solution in THF, 5 mL, 10 mmol, 20.0 eq) washeated at 100° C. for 24 h. The mixture was cooled to RT andconcentrated under reduced pressure. The residue was purified byprep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2 mm column, eluting witha gradient of ACN in water with 0.1% TFA, at a flow rate of 20 mL/min)to afford the compounds of Example 67 (65 mg, 37%) and Example 68 (49.3mg, 28%) as white solids.

Example 67

LCMS: [M+H]⁺ 346.2;

Example 68

LCMS: [M+H]⁺ 346.2; ¹H NMR (400 MHz, DMSO-d₆) δ 12.3 (s, 1H), 9.05 (s,1H), 7.93 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.37 (t, J=7.6 Hz,1H), 3.63 (s, 2H), 3.29-3.22 (m, 1H), 2.97 (d, J=6.4 Hz, 2H), 2.74 (d,J=4.8 Hz, 6H), 2.50 (s, 3H), 1.86-1.78 (m, 1H), 1.78-1.70 (m, 4H),1.57-1.44 (m, 2H), 1.38-1.29 (m, 2H).

Example 69:2-(((trans-4-((Dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one Trifluoroacetate

The compound of Example 67 was further purified by prep-HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, eluting with a gradient of ACN inwater with 0.1% TFA, at a flow rate of 15 mL/min) to afford the titlecompound. LCMS: [M+H]⁺ 346.2.

¹H NMR (400 MHz, DMSO-d₆) δ 12.3 (s, 1H), 9.12 (s, 1H), 7.93 (d, J=8.0Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 3.66 (s, 2H),2.90 (s, 2H), 2.80-2.77 (m, 1H), 2.74 (d, J=4.8 Hz, 6H), 2.51 (s, 3H),2.08 (d, J=11.6 Hz, 2H), 1.82-1.64 (m, 3H), 1.26 (m, 2H), 0.96 (m, 2H).

Example 70:2-(((trans-3-(Hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneand Example 71:2-(((cis-3-(Hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

Step 1:2-(((3-(Hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

To a solution of Int-B13 (316 mg, 1.7 mmol, 1.0 eq) in THF (10 mL) wasadded 1 M NaOH (4 mL) and the mixture was stirred at RT for 10 min undera N₂ atmosphere. Int-A1 (350 mg, 1.7 mmol, 1.0 eq) was then added andthe mixture was stirred at RT overnight under a N₂ atmosphere. Themixture was diluted with water (5 mL) and extracted with EtOAc (20mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (DCM:MeOH, 10:1, v/v) to afford the title compound as a5:1 mixture of cis/trans isomers (200 mg, 38%) as a white solid. LCMS:[M+H]⁺319.1.

Step 2:2-(((trans-3-(Hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneand2-(((cis-3-(Hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one

2-(((3-(Hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one(100 mg) was further purified by prep-HPLC (Agilent 10 prep-C18, 10 μm,250×21.2 mm column, eluting with a gradient of MeOH in water with 0.1%TFA, at a flow rate of 20 mL/min) to afford the compounds of Example 70(2.5 mg) and Example 71 (20 mg).

Example 70

LCMS: [M+H]⁺ 319.1.

¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=8.0 Hz, 1H), 7.63 (d, J=7.2 Hz,1H), 7.38 (t, J=7.6 Hz, 1H), 3.83 (s, 2H), 3.45 (t, J=5.2 Hz, 2H),2.74-2.64 (m, 1H), 2.60 (s, 3H), 2.10 (m, 2H), 1.88-1.69 (m, 2H),1.51-1.45 (m, 1H), 1.35-1.20 (m, 3H), 0.98-0.84 (m, 1H).

Example 71

LCMS: [M+H]⁺ 319.1

¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J=8.0 Hz, 1H), 7.60 (d, J=7.2 Hz,1H), 7.36 (t, J=7.6 Hz, 1H), 3.86-3.70 (m, 2H), 3.55-3.32 (m, 2H),3.24-3.11 (m, 1H), 2.59 (s, 3H), 2.02-1.91 (m, 1H), 1.89-1.81 (m, 1H),1.80-1.60 (m, 5H), 1.60-1.48 (m, 2H).

Example 72:2-((((cis)-3-((Dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-one Trifluoroacetate

Step 1:(3-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methylmethanesulfonate

The title compound was prepared from2-(((3-(hydroxymethyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneaccording to the method described for Example 64, step 1. LCMS: [M+H]⁺397.1.

Step 2:2-((((cis)-3-((Dimethylamino)methyl)cyclohexyl)thio)methyl)-8-methylquinazolin-4(3H)-oneTrifluoroacetate

The title compound was prepared from(3-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methylmethanesulfonate according to the method described for Example 67 andExample 68. The minor trans isomer was not isolated. LCMS: [M+H]⁺ 346.2;

¹H NMR (400 MHz, CD₃OD) δ 8.03 (dd, J=8.0, 1.6 Hz, 1H), 7.67 (d, J=7.2Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 3.75-3.71 (m, 2H), 3.46-3.40 (m, 1H),3.05-2.88 (m, 2H), 2.84 (d, J=5.2 Hz, 6H), 2.58 (s, 3H), 2.25-2.16 (m,1H), 1.93-1.82 (m, 2H), 1.80-1.69 (m, 3H), 1.65-1.50 (m, 2H), 1.18-1.06(m, 1H).

Example 73:8-Methyl-2-(((trans-4-((methylamino)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one

Step 1:(trans-4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methylMethanesulfonate

The title compound was prepared from Example 62 according to the methoddescribed for Example 64, step 1. LCMS: [M+H]⁺ 397.1.

Step 2:8-Methyl-2-(((trans-4-((methylamino)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one

A mixture of(trans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)methyl methanesulfonate (80 mg, 0.2 mmol, 1.0 eq), Et₃N (40mg, 0.2 mmol, 2.0 eq) and methylamine (2 M solution in THF, 5 mL, 10mmol, 50.0 eq) was heated at 90° C. for 2 days. The mixture was cooledto RT and concentrated under reduced pressure. The residue was purifiedby prep-TLC (DCM:MeOH, 10:1, v/v) to afford the title compound (10 mg,15%) as a white solid. LCMS: [M+H]⁺ 332.2.

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.2 Hz,1H), 7.38 (t, J=7.6 Hz, 1H), 3.75 (s, 2H), 2.83 (d, J=7.2 Hz, 2H),2.77-2.70 (m, 1H), 2.67 (s, 3H), 2.58 (s, 3H), 2.23-2.15 (m, 2H),1.88-1.81 (m, 2H), 1.73-1.62 (m, 1H), 1.40-1.29 (m, 2H), 1.13-1.01 (m,2H).

Example 74:7-Amino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1:7-Nitro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from Int-A11 and Int-B1 according to themethod described for Example 28. LCMS: [M+H]⁺ 322.0.

Step 2:7-Amino-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of7-nitro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one(100 mg, 0.31 mmol, 1.0 eq) and NH₄Cl (100 mg, 1.88 mmol, 6.0 eq) inEtOH (3 mL) and water (2 mL) was added Fe (104 mg, 1.88 mmol, 6.0 eq)and the mixture was heated at 80° C. for 2 h. The mixture was cooled toRT, filtered and concentrated under reduced pressure. The residue waspurified by prep-TLC (DCM:MeOH, 60:1, v/v) to afford the title compound(40 mg, 44%) as a white solid. LCMS: [M+H]⁺ 292.1.

¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 6.68(dd, J=8.8, 2.4 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.05 (s, 2H), 3.81 (dt,J=11.6, 3.6 Hz, 2H), 3.57 (s, 2H), 3.33-3.27 (m, 2H), 3.04 (t, J=10.8Hz, 1H), 1.93-1.85 (m, 2H), 1.49-1.39 (m, 2H).

Example 75:N-(4-Oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)acetamide

To a solution of Example 74 (60 mg, 0.21 mmol, 1.0 eq) and Et₃N (42 mg,0.41 mmol, 2.0 eq) in DCM (10 mL) at 0° C. was added AcCl (32 mg, 0.41mmol, 2.0 eq) dropwise and the mixture was warmed to RT and stirred for1 h. The mixture was diluted with water (10 mL), extracted with DCM (20mL×3) and the combined organic layers were washed with water (20 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by prep-TLC (DCM:MeOH, 60:1, v/v) to afford the titlecompound (13 mg, 19%) as an off-white solid. LCMS: [M+H]⁺ 334.1.

¹H NMR (400 MHz, CD₃OD) δ 8.13-8.09 (m, 2H), 7.59 (dd, J=8.8, 1.6 Hz,1H), 3.97-3.82 (m, 2H), 3.72 (s, 2H), 3.51-3.37 (m, 2H), 3.09-2.96 (m,1H), 2.19 (s, 3H), 2.00-1.89 (m, 2H), 1.66-1.50 (m, 2H).

Example 76:N-(4-Oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)benzamide

The title compound was prepared from the compound of Example 74 andbenzoyl chloride according to the method described for Example 75. LCMS:[M+H]⁺ 396.1. ¹HNMR (400 MHz, DMSO-d₆) δ 10.7 (s, 1H), 8.25 (d, J=1.6Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 8.04-7.96 (m, 2H), 7.90 (dd, J=8.8, 2.0Hz, 1H), 7.67-7.60 (m, 1H), 7.60-7.52 (m, 2H), 3.85-3.79 (m, 2H), 3.75(s, 2H), 3.36-3.29 (m, 2H), 3.15-3.07 (m, 1H), 1.99-1.86 (m, 2H),1.53-1.38 (m, 2H).

Example 77:N-Methyl-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxamide

Step 1:4-Oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxylicacid

The title compound was prepared from Int-A16 and Int-B1 according to themethod described for Example 28. This coupling reaction proceeded withconcomitant hydrolysis of the methyl ester to give the title compounddirectly. LCMS: [M+H]⁺ 321.1.

Step 2:N-Methyl-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxamide

To a solution of4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxylicacid (150 mg, 0.47 mmol, 1.0 eq) in DMF (5 mL) at RT under a N₂atmosphere was added MeNH₂ (2 M solution in THF, 0.94 mL, 1.88 mmol, 4.0eq), EDCI (180 mg, 0.94 mmol, 2.0 eq) and HOBt (127 mg, 0.94 mmol, 2.0eq) and the mixture was stirred at RT overnight. The mixture was dilutedwith water (20 mL), extracted with EtOAc (20 mL×3) and the combinedorganic layers were washed with water (20 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-TLC (DCM:MeOH, 10:1, v/v) to afford the title compound (100 mg,64%) as a white solid. LCMS: [M+H]⁺ 334.1.

¹HNMR (400 MHz, DMSO-d₆) δ 12.4 (s, 1H), 8.72 (d, J=4.4 Hz, 1H), 8.15(d, J=8.0 Hz, 1H), 8.05 (s, 1H), 7.93-7.82 (m, 1H), 3.83-3.80 (m, 2H),3.69 (s, 2H), 3.32-3.30 (m, 2H), 3.10-3.04 (m, 1H), 2.82 (d, J=4.8 Hz,3H), 1.90 (d, J=12.2 Hz, 2H), 1.50-1.41 (m, 2H).

Example 78:4-Oxo-N-phenyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxamide

The title compound was prepared from4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-7-carboxylicacid and PhNH₂ according to the method described for Example 77, step 2.LCMS: [M+H]⁺ 396.1.

¹H NMR (400 MHz, DMSO-d₆) δ 12.5 (br s, 1H), 10.5 (s, 1H), 8.22-8.20 (m,2H), 7.98 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.0 Hz, 2H), 7.38 (t, J=8.0 Hz,2H), 7.13 (t, J=7.2 Hz, 1H), 3.83-3.80 (m, 2H), 3.69 (s, 2H), 3.32-3.30(m, 2H), 3.10-3.04 (m, 1H), 1.90 (d, J=12.2 Hz, 2H), 1.50-1.41 (m, 2H).

Example 79:7-(Phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1:7-Bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from Int-A8 and Int-B1 according to themethod described for Example 28. LCMS: [M+H]⁺ 355.0.

Step 2:7-Bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

To a solution of7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one(7.5 g, 21.1 mmol, 1.0 eq) in anhydrous THF (100 mL) at 0° C. under a N₂atmosphere was added LiHMDS (1 M in THF, 42.2 mL, 42.2 mmol, 2.0 eq)dropwise and the mixture was stirred at 0° C. for 1 h. SEMCl (5.3 g,31.7 mmol, 1.5 eq) was added and the mixture was stirred for a further1.5 h. The reaction was quenched with water (30 mL) and the mixture wasextracted with EtOAc (50 mL×3). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by column chromatography (Petroleum ether:EtOAc, 10:1, v/v) toafford the title compound (7.8 g, 76%) as a colorless oil. LCMS: [M+H]⁺485.1.

¹H NMR (400 MHz, CD₃OD) δ 8.12 (d, J=8.4 Hz, 1H), 7.80 (d, J=1.2 Hz,1H), 7.58 (dd, J=8.4, 1.2 Hz, 1H), 5.73 (s, 2H), 3.98-3.94 (m, 4H), 3.66(t, J=8.0 Hz, 2H), 3.45-3.39 (m, 2H), 3.09-3.02 (m, 1H), 1.93 (d, J=13.2Hz, 2H), 1.70-1.62 (m, 2H), 0.93 (t, J=8.0 Hz, 2H), 0.02 (s, 9H).

Step 3:7-(Phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

To a solution of7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (60 mg, 0.12 mmol, 1.0 eq) and PhNH₂ (14 mg,0.15 mmol, 1.2 eq) in toluene (5 mL) under a N₂ atmosphere was addedt-BuONa (35 mg, 0.37 mmol, 3.0 eq), BINAP (15 mg, 0.024 mmol, 0.2 eq)and Pd₂(dba)₃ (11 mg, 0.012 mmol, 0.1 eq) and the mixture was heated atreflux for 3 h. After cooling to RT, the mixture was diluted with water(10 mL) and extracted with EtOAc (15 mL×3). The combined organic layerswere dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-TLC (Petroleum ether:EtOAc, 3:1, v/v) toafford the title compound (40 mg, 60%) as a yellow solid. LCMS: [M+H]⁺498.3.

Step 4:7-(Phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one(60 mg, 0.12 mmol, 1.0 eq) in dioxane (3 mL) was added a 3 M HCl/dioxanesolution (1 mL) and the mixture was heated at 40° C. overnight. Themixture was cooled to RT and concentrated under reduced pressure. Theresidue was purified by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2mm column, eluting with a gradient of ACN in water with 0.1% TFA, at aflow rate of 20 mL/min) to afford the title compound (13 mg, 29%) as alight yellow solid. LCMS: [M+H]⁺ 368.1.

¹H NMR (400 MHz, CD₃OD) δ 7.98 (d, J=8.8 Hz, 1H), 7.39-7.33 (m, 2H),7.26 (d, J=8.0 Hz, 2H), 7.17-7.05 (m, 3H), 3.89 (dt, J=11.6, 4.0 Hz,2H), 3.69 (s, 2H), 3.42 (td, J=11.2, 2.4 Hz, 2H), 3.05-2.98 (m, 1H),1.93 (d, J=13.2 Hz, 2H), 1.62-1.52 (m, 2H).

Example 80:7-(Pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1:7-(Pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

The title compound was prepared from7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one and pyridin-3-amine according to the methoddescribed for Example 79, step 3. LCMS: [M+H]⁺ 499.2.

Step 2:7-(Pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of7-(pyridin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one(30 mg, 0.06 mmol, 1.0 eq) in THF (1 mL) was added 2 M HCl (1 mL) andthe mixture was stirred at RT overnight. The mixture was adjusted pH to8-9 with a saturated aqueous NaHCO₃ solution and extracted with EtOAc(15 mL×3). The combined organic layers were concentrated under reducedpressure and the residue was purified by prep-TLC (DCM:MeOH, 20:1, v/v)to afford the title compound (10 mg, 45%) as a white solid. LCMS: [M+H]⁺369.1.

¹HNMR (400 HMz, DMSO-d₆) δ 12.0 (s, 1H), 9.01 (s, 1H), 8.46 (d, J=4.0Hz, 1H), 8.22 (dd, J=8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.66 (d,J=12.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.13 (dd, J=12.0 Hz, 1H), 7.04 (d,J=4.0 Hz, 1H), 3.85-3.76 (m, 2H), 3.61 (s, 2H), 3.31-3.26 (m, 2H),3.10-3.00 (m, 1H), 1.92-1.84 (m, 2H), 1.49-1.37 (m, 2H).

The following examples in Table 5 were similarly prepared using thetwo-step procedure in Example 80 beginning with7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-oneand the appropriate amine.

TABLE 5 Example Name and structure Amine Example 81

pyridin-2-amine Example 82

4-methoxyaniline Example 83

3-methoxyaniline Example 84

2-methoxyaniline Example 85

pyrazin-2-amine Example 86

pyridin-4-amine Example 87

pyrimidin-5-amine Example 88

1-methyl-1H- imidazol-2-amine Example 89

thiazol-2-amine Example 90

2-methylpyridin-3- amine Example 91

4-methylpyridin-3- amine Example 92

5-methylpyridin-3- amine

Example 93:7-(4-Amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Trifluoroacetate

Step 1.7-(4-Amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

To a solution of7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (50 mg, 0.10 mmol, 1.0 eq) and1H-pyrazol-4-amine (10 mg, 0.12 mmol, 1.2 eq) in toluene (5 mL) under aN₂ atmosphere was added t-BuONa (20 mg, 0.20 mmol, 2.0 eq), t-BuXphos(18 mg, 0.04 mmol, 0.4 eq) and Pd₂(dba)₃ (9 mg, 0.01 mmol, 0.1 eq) andthe mixture was heated at reflux for 24 h. After cooling to RT, themixture was diluted with water (10 mL) and extracted with EtOAc (15mL×3). The combined organic layers were washed with water (10 mL), driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by prep-TLC (Petroleum ether:EtOAc, 3:1, v/v) to afford thetitle compound (19 mg, 40%) as a yellow oil. LCMS: [M+H]⁺ 488.2.

Step 2:7-(4-Amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from7-(4-amino-1H-pyrazol-1-yl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-oneaccording to the method described for Example 80, step 2. LCMS: [M+H]⁺358.1.

¹H NMR (400 MHz, DMSO-d₆) δ 12.4 (br s, 1H), 8.57 (s, 1H), 8.18 (d,J=9.2 Hz, 1H), 7.99-7.97 (m, 2H), 7.78 (s, 1H), 3.86-3.78 (m, 2H), 3.70(s, 2H), 3.36-3.30 (m, 2H), 3.12-3.01 (m, 1H), 1.89 (d, J=11.8 Hz, 2H),1.51-1.42 (m, 2H).

Example 94:7-(Isoxazol-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1:7-(Isoxazol-3-ylamino)-2-(tetrahydropyran-4-ylsulfanylmethyl)-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one

The title compound was prepared from7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one and isoxazol-3-amine according to themethod described for Example 79, step 3. LCMS: [M+H]⁺ 489.2

Step 2:7-(Isoxazol-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

A mixture of7-(isoxazol-3-ylamino)-2-(tetrahydropyran-4-ylsulfanylmethyl)-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one(25 mg, 0.05 mmol, 1.0 eq) and formic acid (1.0 mL) was stirred at RTovernight. The mixture was diluted with MeOH (1 mL) and purified byprep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2 mm column, eluting witha gradient of ACN in water with 0.1% TFA, at a flow rate of 20 mL/min)to afford the title compound (4 mg, 22%) as a white solid. LCMS: [M+H]⁺359.1.

¹H NMR (400 MHz, DMSO-d₆) δ 12.0 (s, 1H), 9.80 (s, 1H), 8.70 (d, J=1.8Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.38 (dd,J=8.8, 2.4 Hz, 1H), 6.30 (d, J=1.6 Hz, 1H), 3.81 (d, J=11.6 Hz, 2H),3.65 (s, 2H), 3.40-3.28 (2H obscured by water peak), 3.06 (td, J=10.8,5.2 Hz, 1H), 1.90 (d, J=13.2 Hz, 2H), 1.61-1.38 (m, 2H).

Example 95:8-Methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1:7-Bromo-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from Int-A24 and Int-B1 according to themethod described for Example 28. LCMS: [M+H]⁺ 369.0.

Step 2:8-Methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

The title compound was prepared from7-bromo-8-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-oneaccording to the method described for Example 79, step 2 and 3. LCMS:[M+H]⁺ 512.1.

Step 3:8-Methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from8-methyl-7-(phenylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-oneaccording to the method described for Example 80, step 2. LCMS: [M+H]⁺382.2.

¹H NMR (400 MHz, CDCl₃) δ 9.77 (s, 1H), 8.02 (d, J=8.8 Hz, 1H),7.40-7.35 (m, 2H), 7.32 (d, J=8.8 Hz, 1H), 7.18 (d, J=7.6 Hz, 2H),7.14-7.09 (m, 1H), 5.90 (s, 1H), 4.00-3.92 (m, 2H), 3.79 (s, 2H),3.41-3.33 (m, 2H), 2.99-2.85 (m, 1H), 2.51 (s, 3H), 1.94 (d, J=14.6 Hz,2H), 1.76-1.61 (m, 2H).

Example 96:7-(Benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1:7-(Benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

To a solution of7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (80 mg, 0.16 mmol, 1.0 eq) and KOH (28 mg,0.49 mmol, 3.0 eq) in dioxane (1 mL) and water (1 mL) under a N₂atmosphere was added Pd₂(dba)₃ (15 mg, 0.016 mmol, 0.1 eq) and t-BuXPhos(25 mg, 0.06 mmol, 0.4 eq) and the mixture was heated at 90° C.overnight. After cooling to RT, BnBr (136 mg, 0.8 mmol, 5.0 eq) andn-Bu₄NBr (257 mg, 0.8 mmol, 5.0 eq) was added and the mixture wasstirred at RT for 6 h. The mixture was diluted with water (20 mL) andextracted with EtOAc (30 mL×3). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by prep-TLC (Petroleum ether:EtOAc, 3:1 to 1:1, v/v) to affordthe title compound (28 mg, 34%) as a gray solid. LCMS: [M+H]⁺ 513.2.

Step 2:7-(Benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of7-(benzyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one(45 mg, 0.09 mmol, 1.0 eq) in DCM (1 mL) was added TFA (1 mL) and themixture was stirred at RT for 2 h. The mixture was concentrated underreduced pressure and the residue was purified by C18 reverse phasecolumn (Biotage, 45%-55% ACN in water) to afford the title compound (6mg, 18%) as a white solid. LCMS: [M+H]⁺ 383.1.

¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, J=8.8 Hz, 1H), 7.46-7.36 (m, 5H),7.19-7.15 (m, 2H), 5.19 (s, 2H), 3.96-3.92 (m, 2H), 3.82 (s, 2H), 3.37(t, J=11.2 Hz, 2H), 2.91-2.84 (m, 1H), 1.92-1.88 (m, 2H), 1.71-1.62 (m,2H).

Example 97:2-(((4-Hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

Step 1:2-((1,4-Dioxaspiro[4,5]decan-8-ylthio)methyl)-7-bromoquinazolin-4(3H)-one

The title compound was prepared from Int-A8 and Int-B6 according to themethod described for Example 28. LCMS: [M+H]⁺ 411.0.

Step 2:2-((1,4-Dioxaspiro[4,5]decan-8-ylthio)methyl)-7-(phenylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

The title compound was prepared from2-((1,4-dioxaspiro[4.5]decan-8-ylthio)methyl)-7-bromoquinazolin-4(3H)-oneaccording to the method described for Example 79, steps 2 and 3. LCMS:[M+H]⁺ 541.1.

Step 3:2-(((4-Oxocyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

To a solution of2-((1,4-dioxaspiro[4.5]decan-8-ylthio)methyl)-7-(phenylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one(100 mg, 0.18 mmol, 1.0 eq) in THF (5 mL) was added 1 M HCl (5 mL) andthe mixture was stirred at RT overnight. The mixture was adjusted pH to8-9 with a saturated aqueous NaHCO₃ solution and extracted with EtOAc(15 mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-TLC (DCM:MeOH, 10:1, v/v) to afford the title compound (28 mg, 41%)as a white solid. LCMS: [M+H]⁺ 450.2.

Step 4:2-(((4-Hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

The title compound was prepared from2-(((4-oxocyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one tothe method described for Example 22. LCMS: [M+H]⁺382.2.

Example 98:2-(((trans-4-Hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-oneand Example 99:2-(((cis-4-Hydroxycyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

The compound of Example 97 was further purified by prep-HPLC (Agilent 10prep-C18, 10 μm, 250×21.2 mm column, eluting with a gradient of MeOH inwater with 0.1% TFA, at a flow rate of 20 mL/min) to afford the titlecompounds.

Example 98

LCMS: [M+H]⁺ 382.2.

¹H NMR (400 MHz, CD₃OD) δ 7.98 (d, J=8.8 Hz, 1H), 7.36 (t, J=7.6 Hz,2H), 7.26 (d, J=7.6 Hz, 2H), 7.16 (d, J=2.0 Hz, 1H), 7.14-7.04 (m, 2H),3.65 (s, 2H), 3.52-2.46 (m, 1H), 2.73-2.65 (m, 1H), 2.05 (d, J=16.0 Hz,2H), 1.94 (d, J=10.4 Hz, 2H), 1.38-1.32 (m, 2H), 1.26-1.22 (m, 2H).

Example 99

LCMS: [M+H]⁺ 382.2.

¹H NMR (400 MHz, CD₃OD) δ 7.97 (d, J=8.4 Hz, 1H), 7.36 (t, J=8.0 Hz,2H), 7.26 (d, J=8.0 Hz, 2H), 7.16 (d, J=2.0 Hz, 1H), 7.14-7.04 (m, 2H),3.72 (s, 1H), 3.64 (s, 2H), 2.97-2.89 (m, 1H), 1.81-1.72 (m, 4H),1.72-1.55 (m, 4H).

Example 100:2-(((cis-4-Hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-oneand Example 101:2-(((trans-4-Hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

Step 1:2-((1,4-Dioxaspiro[4,5]decan-8-ylthio)methyl)-7-(pyridin-3-ylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

The title compound was prepared from2-((1,4-dioxaspiro[4.5]decan-8-ylthio)methyl)-7-bromoquinazolin-4(3H)-oneaccording to the method described for Example 79, steps 2 and 3, usingpyridin-3-amine. LCMS: [M+H]⁺ 425.2.

Step 2:2-(((4-Oxocyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

The title compound was prepared from2-((1,4-dioxaspiro[4.5]decan-8-ylthio)methyl)-7-(pyridin-3-ylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-oneaccording to the method described for Example 97, step 3. LCMS: [M+H]⁺381.2.

Step 3:2-(((4-Hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

The title compound was prepared from2-(((4-oxocyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-oneaccording to the method described for Example 22. LCMS: [M+H]⁺ 383.2.

Step 4:2-(((cis-4-Hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-oneand2-(((trans-4-Hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

2-(((4-Hydroxycyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-onewas further purified by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2mm column, eluting with a gradient of ACN in water with 0.1% TFA, at aflow rate of 20 mL/min) to afford the title compounds.

Example 100

LCMS: [M+H]⁺ 383.2.

¹H NMR (400 MHz, CD₃OD) δ 8.45 (d, J=2.8 Hz, 1H), 8.18 (dd, J=4.8, 1.2Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.82-7.75 (m, 1H), 7.41 (dd, J=8.4, 4.8Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.16 (dd, J=8.8, 2.4 Hz, 1H), 3.72 (d,J=3.2 Hz, 1H), 3.35 (s, 2H), 2.95 (d, J=4.4 Hz, 1H), 1.97-1.45 (m, 8H).

Example 101

LCMS: [M+H]⁺ 383.2.

¹H NMR (400 MHz, CD₃OD) δ 8.45 (d, J=2.4 Hz, 1H), 8.22-8.17 (m, 1H),8.05 (d, J=8.8 Hz, 1H), 7.81-7.75 (m, 1H), 7.42 (dd, J=8.4, 4.8 Hz, 1H),7.22 (d, J=2.0 Hz, 1H), 7.17 (dd, J=8.8, 2.2 Hz, 1H), 3.52 (td, J=10.4,5.2 Hz, 1H), 3.35 (s, 2H), 2.70 (td, J=11.2, 3.6 Hz, 1H), 2.06 (d,J=12.4 Hz, 2H), 1.93 (d, J=11.6 Hz, 2H), 1.40-1.22 (m, 4H).

Example 102:7-(Cyclopentylamino)-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one and Example 103:7-(Cyclopentylamino)-2-(((cis-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

Step 1:2-((1,4-Dioxaspiro[4,5]decan-8-ylthio)methyl)-7-(cyclopentylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

The title compound was prepared from2-((1,4-dioxaspiro[4.5]decan-8-ylthio)methyl)-7-bromoquinazolin-4(3H)-oneand cyclopentanamine amine according to the method described for Example79, step 2, 3. LCMS: [M+H]⁺ 446.3.

Step 2:7-(Cyclopentylamino)-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from2-((1,4-dioxaspiro[4.5]decan-8-ylthio)methyl)-7-(cyclopentylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-oneaccording to the method described for Example 97, step 3. LCMS: [M+H]⁺372.2.

Step 3:7-(Cyclopentylamino)-2-(((4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from7-(cyclopentylamino)-2-(((4-oxocyclohexyl)thio)methyl)quinazolin-4(3H)-oneaccording to the method described for Example 22. LCMS: [M+H]⁺ 374.2.

Step 4:7-(Cyclopentylamino)-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-oneand 7-(Cyclopentylamino)-2-(((cis-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

7-(Cyclopentylamino)-2-(((4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-onewas further purified by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2mm column, eluting with a gradient of ACN in water, at a flow rate of 20mL/min) to afford the title compounds.

Example 102

LCMS: [M+H]⁺ 374.2.

¹HNMR (400 MHz, DMSO-d₆) δ ppm: 11.6 (br s, 1H), 7.70 (d, J=8.0 Hz, 1H),6.69 (dd, J=8.0, 2.0 Hz, 1H), 6.50 (m, 1H), 6.45 (d, J=2.0 Hz, 1H), 4.52(br s, 1H), 3.74-3.82 (m, 1H), 3.52 (s, 2H), 3.39-3.35 (m, 1H),2.76-2.64 (m, 1H), 2.03-1.90 (m, 4H), 1.82-1.76 (m, 2H), 1.73-1.63 (m,2H), 1.62-1.53 (m, 2H), 1.52-1.42 (m, 2H), 1.24-1.13 (m, 4H).

Example 103

LCMS: [M+H]⁺ 374.2.

¹HNMR (400 MHz, DMSO-d₆) δ ppm: 11.6 (br s, 1H), 7.70 (d, J=8.0 Hz, 1H),6.69 (d, J=8.0, 2.0 Hz, 1H), 6.50 (m, 1H), 6.45 (s, 1H), 4.41 (br s,1H), 3.80-3.75 (m, 1H), 3.59-3.56 (m, 1H), 3.51 (s, 2H), 2.97-2.90 (m,1H), 1.97-1.90 (m, 2H), 1.72-1.61 (m, 6H), 1.62-1.42 (m, 8H).

Example 104:2-(((trans-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one and Example 105:2-(((cis-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

Step 1:7-Bromo-2-(((4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one

The title compound were prepared from Int-A8 and Int-B12 according tothe method described in Example 70 and Example 71, step 1, as a 1:1mixture of cis/trans isomers, which was used directly in the next step.

Step 2:2-(((4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-7-(phenylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

The title compound was prepared from7-bromo-2-(((4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one according to the method described forExample 79, step 2 and 3. LCMS: [M+H]⁺ 640.3.

Step 3:2-(((4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

To a solution of2-(((4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-7-(phenylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one(600 mg, 0.94 mmol, 1.0 eq) in THF (4 mL) was added 2 M HCl (4 mL) andthe mixture was stirred at RT overnight. The mixture was adjusted to pH8-9 with a saturated aqueous NaHCO₃ solution and extracted with EtOAc(15 mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-TLC (DCM:MeOH, 50:1, v/v) to afford the title compound (90 mg,trans/cis=3:1, 24%) as a white solid. LCMS: [M+H]⁺ 396.2.

Step 4:2-(((trans-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one and2-(((cis-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-one

2-(((4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(phenylamino)quinazolin-4(3H)-onewas further purified by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2mm column, eluting with a gradient of ACN in water with 0.1% TFA, at aflow rate of 20 mL/min) to afford the title compounds.

Example 104

LCMS: [M+H]⁺ 396.2.

¹H NMR (400 MHz, DMSO-d₆) δ 11.9 (br s, 1H), 8.87 (s, 1H), 7.88 (d,J=8.8 Hz, 1H), 7.35 (t, J=7.6 Hz, 2H), 7.22 (d, J=7.6 Hz, 2H), 7.10-6.99(m, 3H), 3.51 (s, 2H), 3.30 (1H (OH) may be obscured by water peak),3.17 (d, J=5.2 Hz, 2H), 2.67 (t, J=6.8 Hz, 1H), 2.00 (d, J=10.8 Hz, 2H),1.73 (d, J=11.2 Hz, 2H), 1.35-1.31 (m, 1H), 1.21-1.11 (m, 2H), 0.94-0.85(m, 2H).

Example 105

LCMS: [M+H]⁺ 396.2.

¹H NMR (400 MHz, DMSO-d₆) δ 12.1 (br s, 1H), 8.89 (s, 1H), 7.89 (d,J=8.8 Hz, 1H), 7.36 (t, J=7.6 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.10-7.00(m, 3H), 3.55 (t, J=6.0 Hz, 2H), 3.30 (1H (OH) may be obscured by waterpeak), 3.22-3.17 (m, 3H), 1.75-1.65 (m, 4H), 1.48-1.37 (m, 3H),1.32-1.23 (m, 2H).

Example 106:2-(((cis-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one and Example 107:2-(((trans-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

Step 1:2-(((4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

The title compound was prepared from7-bromo-2-(((4-((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one and pyridin-3-amine according to the methoddescribed for Example 79, step 2 and 3. LCMS: [M+H]⁺ 641.3.

Step 2:2-(((4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

The title compound was prepared from2-(((4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-oneaccording to the method described for Example 104 and Example 105, step3. LCMS: [M+H]⁺ 397.2.

Step 3:2-(((cis-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one and2-(((trans-4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-one

2-(((4-(Hydroxymethyl)cyclohexyl)thio)methyl)-7-(pyridin-3-ylamino)quinazolin-4(3H)-onewas further purified by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2mm column, eluting with a gradient of ACN in water with 0.1% TFA, at aflow rate of 20 mL/min) to afford the title compounds.

Example 106

LCMS: [M+H]⁺ 397.2.

¹HNMR (400 MHz, CD₃OD) δ 8.45 (d, J=4.0 Hz, 1H), 8.20 (d, J=4.0 Hz, 1H),8.04 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.44-7.40 (m, 1H), 7.21(s, 1H), 7.17 (d, J=8.0 Hz, 1H), 3.63 (s, 2H), 3.37 (d, J=4.0 Hz, 2H),3.20-3.16 (m, 1H), 2.05-2.00 (m, 1H), 1.84-1.70 (m, 4H), 1.45-1.29 (m,4H).

Example 107

LCMS: [M+H]⁺ 397.2.

¹HNMR (400 MHz, CD₃OD) δ 8.46 (d, J=2.4 Hz, 1H), 8.21 (dd, J=4.8, 1.2Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.79 (d, J=10.0 Hz, 1H), 7.42 (m, 1H),7.22 (s, 1H), 7.18 (dd, J=8.8, 2.4 Hz, 1H), 3.70 (s, 2H), 3.32 (m, 2H),2.66 (m, 1H), 2.07 (d, J=12.4 Hz, 2H), 1.82 (d, J=13.2 Hz, 2H), 1.59 (m,1H), 1.33-1.24 (m, 2H), 1.06-0.94 (m, 2H).

Example 108:7-(Cyclohexylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

A mixture of the compound of Example 30 (100 mg, 0.34 mmol, 1.0 eq) andcyclohexanamine (2 mL) was heated at 120° C. for 2 days in a sealedtube. The mixture was allowed to cool to RT and concentrated underreduced pressure. The residue was diluted with water (20 mL) andextracted with EtOAc (30 mL×3). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by prep-TLC (Petroleum ether:EtOAc, 3:1 to 1:1, v/v) to affordthe title compound (35 mg, 28%) as a gray solid. LCMS: [M+H]⁺ 374.2.¹HNMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 6.72(d, J=8.8 Hz, 1H), 6.49 (s, 1H), 6.46 (d, J=7.6 Hz, 1H), 3.83-3.79 (m,2H), 3.58 (s, 2H), 3.34-3.29 (m, 3H), 3.08-3.00 (m, 1H), 1.95-1.86 (m,4H), 1.76-1.71 (m, 2H), 1.63-1.59 (m, 1H), 1.49-1.33 (m, 4H), 1.23-1.14(m, 3H).

The following examples in Table 6 were similarly prepared from Example30 and the appropriate amine according to the method described forExample 108.

TABLE 6 Example Name and structure Amine Example 109

dimethylamine Example 110

methylamine Example 111

morpholine Example 112

1-methylpiperazine Example 113

1-methylpiperidin-4- amine Example 114

tetrahydro-2H-pyran-4- amine Example 115

cyclopentanamine Example 116

propan-2-amine Example 117

pyridin-4-ylmethanamine Example 118

pyridin-3-ylmethanamine Example 119

phenylmethanamine Example 120

1-phenylethan-1-amine Example 121

tetrahydrofuran-3-amine Example 122

cyclobutanamine Example 123

pyridin-3-ylmethanamine Example 124

cyclopropanamine Example 125

N-methylcyclohexanamine

Example 126:7-[(1-Benzyl-3-piperidyl)amino]-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one

A mixture of the compound of Example 30 (150 mg, 0.5 mmol, 1.0 eq) and1-benzylpiperidin-3-amine (1 mL) was heated at 120° C. in a sealed tubefor 2 days. The mixture was allowed to cool to RT, diluted with water(20 mL) and extracted with EtOAc (30 mL×3). The combined organic layerswere dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-TLC (DCM:MeOH, 10/1, v/v) to afford thetitle compound (70 mg, 30%) as yellow solid. LCMS: [M+H]⁺ 465.2.

¹H-NMR: (400 MHz, CD₃OD) δ 7.85 (d, J=4.8 Hz, 1H), 7.40-7.23 (m, 5H),6.86 (dd, J=2.4 Hz, 9.2 Hz, 1H), 6.32 (s, 1H), 3.94-3.85 (m, 2H), 3.67(s, 2H), 3.66-3.54 (m, 3H), 3.46-3.37 (m, 2H), 3.09-2.96 (m, 2H),2.84-2.74 (m, 1H), 2.27-2.17 (m, 1H), 2.16-2.06 (m, 1H), 2.05-1.97 (m,1H), 1.97-1.90 (m, 2H), 1.85-1.76 (m, 1H), 1.75-1.65 (m, 1H), 1.63-1.51(m, 2H), 1.45-1.33 (m, 1H).

Example 127:7-(3-Piperidylamino)-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one

To a solution of the compound of Example 126 (65 mg, 0.14 mmol, 1.0 eq)in DCE (3 mL) was added 1-chloroethyl carbonochloridate (80 mg, 0.56mmol, 4.0 eq) and DIPEA (0.1 mL, 0.56 mmol, 4.0 eq). The mixture wasstirred at 25° C. for 48 h and then concentrated under reduced pressure.Methanol (5 mL) was added and the mixture was heated at reflux for 2 h,then allowed to cool to RT and concentrated under reduced pressure. Theresidue was purified by prep-TLC (DCM/MeOH=10/1, v/v) to afford thetitle compound (10 mg, 19%) as a yellow solid. LCMS: [M+H]⁺ 375.2.

¹H-NMR: (400 MHz, DMSO-d₆) δ 11.7 (br s, 1H), 7.78 (d, J=8.8 Hz, 1H),6.78 (dd, J=2.0 Hz, 8.8 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.62 (d, J=1.6Hz, 1H), 3.86-3.76 (m, 2H), 3.75-3.67 (m, 1H), 3.60 (s, 2H), 3.19-3.11(m, 2H), 3.07-2.98 (m, 2H), 2.85-2.76 (m, 2H), 2.68-2.57 (m, 2H),2.01-1.92 (m, 1H), 1.87 (d, J=12.0 Hz, 3H), 1.77-1.64 (m, 1H), 1.57-1.38(m, 3H).

Example 128:7-((1-Benzylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from the compound of Example 30 and1-benzylpiperidin-4-amine according to the method described for Example126. LCMS: [M+H]⁺ 465.2.

¹H NMR (400 MHz, CD₃OD) δ 7.88 (d, J=8.8 Hz, 1H), 7.49-7.35 (m, 5H),6.82 (dd, J=8.9, 2.0 Hz, 1H), 6.65 (d, J=1.6 Hz, 1H), 3.99-3.86 (m, 4H),3.68 (s, 2H), 3.65-3.54 (m, 1H), 3.47-3.37 (m, 2H), 3.27-3.16 (m, 2H),3.07-2.97 (m, 1H), 2.81-2.64 (m, 2H), 2.23-2.10 (m, 2H), 1.99-1.89 (m,2H), 1.79-1.64 (m, 2H), 1.66-1.50 (m, 2H).

Example 129:7-(Piperidin-4-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from Example 128 according to the methoddescribed for Example 127. LCMS: [M+H]⁺ 375.1.

¹H NMR (400 MHz, CD₃OD) δ 7.91 (d, J=4.8 Hz 1H), 6.87-6.85 (m, 1H),6.71-6.68 (m, 1H), 3.93-3.86 (m, 2H), 3.83-3.74 (m, 1H), 3.70 (s, 2H),3.56-3.39 (m, 4H), 3.24-3.17 (m, 2H), 3.08-2.95 (m, 1H), 2.30-2.26 (m,2H), 1.93 (d, J=6.8 Hz, 2H), 1.79-1.69 (m, 2H), 1.63-1.55 (m, 2H).

Example 130:7-(Pyrrolidin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1:7-((1-Benzylpyrrolidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from Example 30 and1-benzylpyrrolidin-3-amine according to the method described for Example126. LCMS: [M+H]⁺ 451.2.

Step 2.7-(Pyrrolidin-3-ylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from7-((1-benzylpyrrolidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one according to the method described for Example 127.LCMS: [M+H]⁺ 361.2.

¹H NMR (400 MHz, CDCl₃) δ 7.98-7.91 (m, 1H), 6.91-6.85 (m, 1H), 6.69 (d,J=10.4 Hz, 1H), 4.39-4.32 (m, 1H), 3.93-3.86 (m, 2H), 3.72 (s, 2H),3.60-3.54 (m, 1H), 3.45-3.31 (m, 4H), 3.31-3.22 (m, 1H), 3.07-2.97 (m,1H), 2.39-2.25 (m, 1H), 2.21-2.09 (m, 1H), 1.90 (d, J=6.4, 2H),1.64-1.52 (m, 2H).

Example 131:7-((1-Acetylpiperidin-4-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

A solution of Example 30 (110 mg, 0.37 mmol, 1.0 eq) and1-(4-aminopiperidin-1-yl)ethanone (53 mg, 0.37 mmol, 1.0 eq) in THF (10mL) was heated at 120° C. in a sealed tube for 2 days. The mixture wasallowed to cool to RT, diluted with water (20 mL) and extracted withEtOAc (30 mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-TLC (DCM:MeOH, 10/1, v/v) to afford the title compound (20 mg, 12%)as a white solid. LCMS: [M+H]⁺ 417.2.

¹H NMR (400 MHz, DMSO-d₆) δ 11.9 (s, 1H), 7.93-7.72 (m, 2H), 7.13 (dd,J=9.2, 2.4 Hz, 1H), 6.90-6.85 (m, 1H), 3.95-3.85 (m, 2H), 3.85-3.75 (m,3H), 3.61 (s, 2H), 3.36-3.34 (m, 1H), 3.31-3.27 (m, 1H), 3.10-2.95 (m,3H), 1.94-1.84 (m, 2H), 1.84-1.81 (m, 2H), 1.79 (s, 3H), 1.35-1.51 (m,4H).

Example 132:7-((1-Acetylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from the compound of Example 30 and1-(3-aminopiperidin-1-yl)ethanone according to the method described forExample 131. LCMS: [M+H]⁺ 417.2.

¹H NMR (400 MHz, DMSO-d₆) δ 11.8 (s, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.84(d, J=9.2 Hz, 1H), 7.09 (dd, J=9.2, 2.4 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H),3.86-3.72 (m, 4H), 3.72-3.65 (m, 1H), 3.60 (s, 2H), 3.34-3.27 (m, 2H),3.09-2.96 (m, 2H), 2.86-2.76 (m, 1H), 1.93-1.81 (m, 3H), 1.87 (s, 3H),1.79-1.72 (m, 1H), 1.56-1.38 (m, 4H).

Example 133:7-((1-Methylpiperidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from the compound of Example 127 andformaldehyde according to the method described for Example 14. LCMS:[M+H]⁺ 389.2.

¹H NMR (400 MHz, CDCl₃) δ 9.85 (s, 1H), 7.59 (d, J=8.8 Hz, 1H), 6.68 (d,J=7.6 Hz, 1H), 6.64 (s, 1H), 3.92 (d, J=10.4 Hz, 2H), 3.85-3.78 (m, 1H),3.75 (s, 2H), 3.36 (t, J=10.8 Hz, 2H), 2.93-2.83 (m, 2H), 2.80-2.63 (m,2H), 2.44-2.25 (m, 4H), 1.97-1.85 (m, 4H), 1.66-1.54 (m, 4H).

Example 134:7-((1-Acetylpyrrolidin-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from the compound of Example 130according to the method described for Example 17. LCMS: [M+H]⁺ 403.2.

¹H NMR (400 MHz, CD₃OD) δ 7.97-7.87 (m, 1H), 6.90-6.81 (m, 1H), 6.68 (s,1H), 4.58 (s, 2H), 4.23 (m, 1H), 3.91 (m, 2H), 3.69 (s, 3H), 3.58 (t,J=7.2 Hz, 1H), 3.44 (m, 3H), 3.07-2.97 (m, 1H), 2.31 (m, 1H), 2.15-1.98(m, 3H), 1.94 (m, 2H), 1.58 (m, 2H).

Example 135:8-Methyl-7-phenoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of the compound of Example 33 (108 mg, 0.35 mmol, 1.0 eq)and PhOH (70 mg, 0.74 mmol, 2.1 eq) in DMSO (1 mL) under a N₂ atmospherewas added K₂CO₃ (99 mg, 0.72 mmol, 2.0 eq) and the mixture was heated at120° C. overnight. The mixture was allowed to cool to RT, diluted withwater (20 mL) and extracted with EtOAc (20 mL×3). The combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by prep-TLC (Petroleum ether:EtOAc, 5:1, v/v)followed by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2 mm column,eluting with a gradient of ACN in water, at a flow rate of 20 mL/min) toafford the title compound (1 mg, 1%) as a white solid. LCMS: [M+H]⁺383.2.

¹H NMR (400 MHz, CD₃OD) δ 8.01 (d, J=8.8 Hz, 1H), 7.43-7.36 (m, 2H),7.17 (t, J=7.2 Hz, 1H), 7.03-6.96 (m, 3H), 3.97-3.89 (m, 2H), 3.77 (s,2H), 3.51-3.38 (m, 2H), 3.15-3.13 (m, 1H), 2.51 (s, 3H), 2.01 (d, J=11.6Hz, 2H), 1.68-1.55 (m, 2H).

Example 136:7-(Cyclohexylamino)-2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one and Example 137:7-(Cyclohexylamino)-2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one

Step 1:2-(((4-(((tert-Butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-7-fluoroquinazolin-4(3H)-one

The title compound was prepared from Int-A9 and Int-B12 according to themethod described for Example 28. LCMS: [M+H]⁺ 437.2.

Step 2:7-(Cyclohexylamino)-2-(((4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one

The title compound was prepared from2-(((4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)thio)methyl)-7-fluoroquinazolin-4(3H)-oneand cyclohexanamine according to the method described for Example 108.Loss of the TBS protecting group occurred in this reaction. LCMS: [M+H]⁺437.2.

Step 3:7-(Cyclohexylamino)-2-(((trans-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-oneand7-(Cyclohexylamino)-2-(((cis-4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-one

7-(Cyclohexylamino)-2-(((4-(hydroxymethyl)cyclohexyl)thio)methyl)quinazolin-4(3H)-onewas purified by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2 mmcolumn, eluting with a gradient of MeOH in water with 0.1% TFA, at aflow rate of 20 mL/min) to afford the title compounds.

Example 136

LCMS: [M+H]⁺ 402.2.

¹H NMR (400 MHz, CD₃OD) δ 7.84 (d, J=8.8 Hz, 1H), 6.78 (dd, J=8.8, 2.0Hz, 1H), 6.60 (s, 1H), 3.66 (s, 2H), 3.39-3.32 (m, 3H), 2.71-2.61 (m,1H), 2.12-2.01 (m, 4H), 1.87-1.77 (m, 4H), 1.74-1.66 (m, 1H), 1.49-1.37(m, 3H), 1.31-1.21 (m, 5H), 1.05-0.96 (m, 2H).

Example 137

LCMS: [M+H]⁺ 402.2.

¹H NMR (400 MHz, CD₃OD) δ 7.84 (d, J=8.8 Hz, 1H), 6.78 (dd, J=8.8, 2.4Hz, 1H), 6.60 (s, 1H), 3.61 (s, 2H), 3.38 (m, 3H), 3.21-3.15 (m, 1H),2.10-2.04 (m, 2H), 1.88-1.63 (m, 7H), 1.61-1.38 (m, 7H), 1.26-1.21 (m,3H).

Example 138:8-Methyl-2-(((1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one Bistrifluoroacetate

To a solution of Example 13 (53 mg, 0.17 mmol, 1.0 eq) and1-methyl-1H-imidazole-2-carbaldehyde (28 mg, 0.25 mmol, 1.5 eq) in THF(2 mL) under a N₂ atmosphere was added NaBH(OAc)₃ (72 mg, 0.34 mmol, 2.0eq) and the mixture was stirred at RT overnight. The mixture waspurified by C18 reverse phase column (Biotage, 30% to 70% ACN in water,0.1% TFA) to afford the title compound (22 mg, 34%) as a white solid.LCMS: [M+H]⁺ 384.2.

¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=8.4 Hz, 1H), 7.65 (d, J=7.2 Hz,1H), 7.41 (s, 2H), 7.20 (s, 1H), 4.78 (s, 2H), 3.98 (s, 3H), 3.80 (s,2H), 3.40 (m, 2H), 3.17-3.00 (m, 3H), 2.59 (s, 3H), 2.24 (m, 2H), 1.95(m, 2H).

The following examples in Table 7 were similarly prepared from Example13 and the appropriate aldehyde according to the method described forExample 138.

TABLE 7 Example Name and structure Aldehyde Example 139

N-(4- formylphenyl)acetamide Example 140

4- (dimethylamino) benzaldehyde Example 141

4-formylbenzonitrile Example 142

1H-pyrazole-3- carbaldehyde Example 143

1-methyl-1H-indazole-3- carbaldehyde Example 144

1,3-dimethyl-1H- pyrazole-4-carbaldehyde Example 145

6-methylpicolinaldehyde Example 146

3-methylpicolinaldehyde Example 147

2-phenylacetaldehyde Example 148

1-methyl-1H-indazole-5- carbaldehyde Example 149

3-methyl-1H-pyrazole-4- carbaldehyde Example 150

N-(3- formylphenyl)acetamide Example 151

1H-pyrrolo[3,2-c] pyridine-3-carbaldehyde Example 152

imidazo[1,2-a]pyridine-3- carbaldehyde Example 153

1-benzyl-1H-imidazole-5- carbaldehyde Example 154

1-benzyl-1H-pyrazole-4- carbaldehyde Example 155

2-(2- formylphenoxy)acetonitrile Example 156

2-oxoindoline-6- carbaldehyde Example 157

5-methoxypicolinaldehyde Example 158

4-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazine-7- carbaldehyde

Example 159:(S)-2-(((1-(2,3-Dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one Trifluoroacetate

The title compound was prepared from the compound of Example 13 and(R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde according to the methoddescribed for Example 138. Purification by C18 reverse phase column(Biotage, 40% to 60% ACN in water, 0.1% TFA) resulted in loss of theprotecting group and gave the title compound directly. LCMS: [M+H]⁺364.2.

¹H NMR (400 MHz, CD₃OD) δ 8.04 (d, J=8.0 Hz, 1H), 7.67 (d, J=7.2 Hz,1H), 7.40 (t, J=7.6 Hz, 1H), 4.06-3.97 (m, 1H), 3.85-3.77 (m, 2H),3.74-3.61 (m, 2H), 3.59-3.38 (m, 3H), 3.22-2.94 (m, 4H), 2.60 (s, 3H),2.45-1.99 (m, 2H), 1.92-1.75 (m, 2H).

Example 160:(R)-2-(((1-(2,3-Dihydroxypropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one Trifluoroacetate

The title compound was prepared from Example 13 and(S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde according to the methoddescribed for Example 138. Purification by C18 reverse phase column(Biotage, 40% to 60% ACN in water, 0.1% TFA) resulted in loss of theprotecting group and gave the title compound directly. LCMS: [M+H]⁺364.2;

¹H NMR (400 MHz, CD₃OD) δ 8.04 (d, J=8.0 Hz, 1H), 7.67 (d, J=7.2 Hz,1H), 7.40 (t, J=7.6 Hz, 1H), 4.06-3.97 (m, 1H), 3.85-3.77 (m, 2H),3.74-3.61 (m, 2H), 3.59-3.38 (m, 3H), 3.22-2.94 (m, 4H), 2.60 (s, 3H),2.45-1.99 (m, 2H), 1.92-1.75 (m, 2H).

Example 161:(S)-8-Methyl-2-(((1-(pyrrolidin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one Hydrochloride

Step 1: (S)-tert-Butyl2-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate

The title compound was prepared from the compound of Example 13 and(S)-tert-butyl 2-formylpyrrolidine-1-carboxylate according to the methoddescribed for Example 138. LCMS: [M+H−56]⁺ 417.3.

Step 2:(S)-8-Methyl-2-(((1-(pyrrolidin-2-ylmethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-oneHydrochloride

The title compound was prepared from (S)-tert-butyl2-((4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate according to the methoddescribed for Example 48, step 2. LCMS: [M+H]⁺ 373.2.

¹H NMR (400 MHz, CD₃OD) δ 8.09 (d, J=7.6 Hz, 1H), 7.75 (d, J=7.2 Hz,1H), 7.50 (t, J=7.2 Hz, 1H), 4.16 (m, 1H), 3.83 (m, 1H), 3.68 (t, J=4.8Hz, 2H), 3.63 (m, 2H), 3.56 (t, J=4.8 Hz, 2H), 3.42 (m, 2H), 3.20 (m,2H), 2.65 (s, 3H), 2.40 (m, 3H), 2.14-1.90 (m, 4H), 1.82 (m, 1H).

Example 162:2-(((1-(2-Hydroxyethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

The title compound was prepared from the compound of Example 13 and2-((tert-butyldimethylsilyl)oxy)acetaldehyde according to the methoddescribed for Example 138. Purification by prep-TLC (DCM:MeOH, 10:1,v/v) resulted in loss of the protecting group and gave the titlecompound directly. LCMS: [M+H]⁺ 334.2.

¹H NMR (400 MHz, CD₃OD) δ 8.02 (d, J=8.0 Hz, 1H), 7.65 (d, J=7.2 Hz,1H), 7.37 (t, J=7.6 Hz, 1H), 3.75 (s, 2H), 3.71 (t, J=5.6 Hz, 2H), 3.10(d, J=12.0 Hz, 2H), 3.00-2.89 (m, 1H), 2.70 (t, J=5.6 Hz, 2H), 2.58 (s,3H), 2.49-2.36 (m, 2H), 2.18-2.08 (m, 2H), 1.78-1.63 (m, 2H).

Example 163:2-(((1-(2-Aminoethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-oneDihydrochloride

Step 1: tert-Butyl(2-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)carbamate

The title compound was prepared from the compound of Example 13 andtert-butyl (2-oxoethyl)carbamate according to the method described forExample 138. LCMS: [M+H]⁺ 433.2

Step 2:2-(((1-(2-Aminoethyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-oneDihydrochloride

The title compound was prepared from tert-butyl(2-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)carbamate according to the method described forExample 48, step 2. LCMS: [M+H]⁺ 333.2.

¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, J=7.6 Hz, 1H), 7.77 (d, J=6.8 Hz,1H), 7.53 (t, J=7.6 Hz, 1H), 3.71 (d, J=11.2 Hz, 2H), 3.58-3.42 (m, 6H),3.27-3.08 (m, 3H), 2.65 (s, 3H), 2.47-2.34 (m, 2H), 2.12-1.92 (m, 2H).

Example 164:N-(2-(4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)ethyl)picolinamide

To a solution of the compound of Example 163 (40 mg, 0.12 mmol, 1.0 eq),picolinic acid (16 mg, 0.13 mmol, 1.1 eq) and DIPEA (47 mg, 0.36 mmol,3.0 eq) in DCM (3 mL) at RT under a N₂ atmosphere was added EDCI (25 mg,0.13 mmol, 1.1 eq) and HOBt (18 mg, 0.13 mmol, 1.1 eq) and the mixturewas stirred overnight. The mixture was diluted with water (40 mL),extracted with EtOAc (20 mL×3) and the combined organic layers werewashed with water (15 mL), dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by prep-TLC (DCM:MeOH, 10:1,v/v) to afford the title compound (10 mg, 17%) as a white solid. LCMS:[M+H]⁺ 438.2.

¹H NMR (400 MHz, CD₃OD) δ 8.62 (d, J=4.0 Hz, 1H), 8.08 (d, J=7.6 Hz,1H), 8.03 (d, J=7.6 Hz, 1H), 7.98-7.92 (m, 1H), 7.65 (d, J=7.2 Hz, 1H),7.57-7.51 (m, 1H), 7.38 (t, J=7.6 Hz, 1H), 3.75 (s, 2H), 3.58 (t, J=6.4Hz, 2H), 3.10-3.00 (m, 2H), 2.96-2.85 (m, 1H), 2.69 (t, J=6.4 Hz, 2H),2.57 (s, 3H), 2.29 (m, 2H), 2.11 (m, 2H), 1.72-1.60 (m, 2H).

Example 165:2-(((1-(3-Aminopropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-oneDihydrochloride

Step 1: tert-Butyl(3-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)propyl)carbamate

The title compound was prepared from the compound of Example 13 andtert-butyl (3-oxopropyl)carbamate according to the method described forExample 138. LCMS: [M+H]⁺447.2.

Step 2:2-(((1-(3-Aminopropyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-oneDihydrochloride

The title compound was prepared from tert-butyl(3-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)propyl)carbamate according to the method described forExample 48, step 2. LCMS: [M+H]⁺ 347.2.

¹H NMR (400 MHz, CD₃OD) δ 8.01 (d, J=7.6 Hz, 1H), 7.63 (d, J=7.2 Hz,1H), 7.36 (t, J=8.0 Hz, 1H), 3.73 (s, 2H), 2.97-2.69 (m, 5H), 2.56 (s,3H), 2.39 (t, J=8.0 Hz, 2H), 2.12-1.99 (m, 4H), 1.76-1.52 (m, 4H).

Example 166:2-(((1-Glycylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-oneHydrochloride

Step 1: tert-Butyl(2-(4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-oxoethyl)carbamate

To a solution of 2-((tert-butoxycarbonyl)amino)acetic acid (36 mg, 0.20mmol, 1.1 eq) and DIPEA (72 mg, 0.55 mmol, 3.0 eq) in NMP (5 mL) at RTunder a N₂ atmosphere was added HATU (105 mg, 0.28 mmol, 1.5 eq) and themixture was stirred for 1 h before adding Example 13 (60 mg, 0.19 mmol,1.0 eq). The mixture was stirred at RT overnight and then diluted withwater (10 mL) and extracted with EtOAc (30 mL×3). The combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by column chromatography (Petroleumether:EtOAc, 3:1, v/v) to afford the title compound (50 mg, 61%) as ayellow solid. LCMS: [M+H]⁺ 447.2.

Step 2:2-(((1-Glycylpiperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-oneHydrochloride

The title compound was prepared from tert-butyl(2-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-2-oxoethyl)carbamate according to the method describedfor Example 48, step 2. LCMS: [M+H]⁺ 347.2.

¹H NMR (400 MHz, CD₃OD) δ 8.11 (d, J=8.0 Hz, 1H), 7.77 (s, 1H),7.56-7.48 (m, 1H), 4.29 (m, 1H), 4.04-3.85 (m, 3H), 3.71 (m, 1H),3.36-3.34 (m, 1H), 3.26-3.16 (m, 2H), 3.02 (t, J=12.1 Hz, 1H), 2.65 (s,3H), 2.18-2.16 (m, 2H), 1.69-1.46 (m, 2H).

Example 167:2-(((1-(3-Aminopropanoyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-oneHydrochloride

The title compound was prepared from the compound of Example 13 and3-((tert-butoxycarbonyl)amino)propanoic acid according to the methoddescribed for Example 166. LCMS: [M+H]⁺ 361.2.

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=7.6 Hz, 1H), 7.66 (d, J=7.2 Hz,1H), 7.39 (t, J=7.6 Hz, 1H), 4.34-4.26 (m, 1H), 3.87-3.75 (m, 3H),3.22-3.10 (m, 4H), 2.97-2.88 (m, 1H), 2.74 (t, J=12.4 Hz, 2H), 2.59 (s,3H), 2.16-2.05 (m, 2H), 1.61-1.44 (m, 2H).

Example 168:2-(((1-(3-(Dimethylamino)propanoyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

The title compound was prepared from the compound of Example 167 andformaldehyde according to the method described for Example 14. LCMS:[M+H]⁺ 389.2.

¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J=7.6 Hz, 1H), 7.64 (d, J=7.2 Hz,1H), 7.40 (t, J=7.6 Hz, 1H), 4.26 (m, 1H), 3.82 (s, 2H), 3.77 (m, 1H),3.22-3.05 (m, 2H), 3.04-2.90 (m, 5H), 2.88 (s, 6H), 2.59 (s, 3H),2.14-1.95 (m, 2H), 1.69-1.47 (m, 2H).

Example 169:(R)-1-(4-Amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine Trihydrochloride

Step 1: (R)-tert-Butyl(5-guanidino-1-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-1-oxopentan-2-yl)carbamate

To a solution of the compound of Example 13 (100 mg, 0.33 mmol, 1.0 eq),(R)-2-((tert-butoxycarbonyl)amino)-5-guanidinopentanoic acid (93 mg,0.33 mmol, 1.0 eq) and DIPEA (213 mg, 1.65 mmol, 5.0 eq) in DMF (4 mL)at RT under a N₂ atmosphere was added BOP (146 mg, 0.36 mmol, 1.1 eq)and the mixture was stirred for 5 h. The mixture was diluted with water(40 mL), extracted with EtOAc (30 mL×3) and the combined organic layerswere dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-TLC (DCM:MeOH, 10:1, v/v) to afford thetitle compound (85 mg, 52%) as a white solid. LCMS: [M+H]⁺546.3.

Step 2:(R)-1-(4-Amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidine Trihydrochloride

The title compound was prepared from (R)-tert-butyl(5-guanidino-1-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-1-oxopentan-2-yl)carbamate according to themethod described for Example 48, step 2. LCMS: [M+H]⁺ 446.3;

¹H NMR (400 MHz, CD₃OD) δ 8.12 (d, J=8.0 Hz, 1H), 7.81-7.76 (m, 1H),7.58-7.50 (m, 1H), 4.55-4.45 (m, 1H), 4.42-4.17 (m, 1H), 3.92 (m, 1H),3.34-3.18 (m, 6H), 3.23-2.96 (m, 1H), 2.66 (d, J=4.0 Hz, 3H), 2.25-2.11(m, 2H), 1.89 (m, 2H), 1.77-1.46 (m, 4H).

Example 170:(S)-1-(4-Amino-5-(4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidin-1-yl)-5-oxopentyl)guanidineTrihydrochloride

The title compound was prepared from the compound of Example 13 and(S)-2-((tert-butoxycarbonyl)amino)-5-guanidinopentanoic acid accordingto the method described for Example 169. LCMS: [M+H]⁺ 446.3.

¹H NMR (400 MHz, CD₃OD) δ 8.12-8.04 (m, 1H), 7.78-7.70 (m, 1H),7.54-7.43 (m, 1H), 4.55-4.45 (m, 1H), 4.42-4.17 (m, 1H), 3.92 (m, 1H),3.34-3.18 (m, 6H), 3.23-2.96 (m, 1H), 2.66 (br s, 3H), 2.26-2.07 (m,2H), 1.85 (m, 2H), 1.75-1.45 (m, 4H).

Example 171:2-(((1-(L-Lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-oneDihydrochloride

The title compound was prepared from the compound of Example 13 and(S)-2,6-bis((tert-butoxycarbonyl)amino)hexanoic acid according to themethod described for Example 166. LCMS: [M+H]⁺ 418.2.

¹H NMR (400 MHz, DMSO-d₆) δ 12.5 (br s, 1H), 8.30 (s, 3H), 8.17 (s, 3H),7.93 (d, J=7.6 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H),4.41-4.27 (m, 1H)), 4.27-4.05 (m, 1H), 3.91-3.78 (m, 1H), 3.76 (s, 2H),3.25-3.11 (m, 2H), 3.03-2.77 (m, 1H), 2.80-2.66 (m, 2H), 2.51 (s, 3H),2.13-1.99 (m, 2H), 1.73-1.61 (m, 2H), 1.57-1.27 (m, 6H).

Example 172:2-(((1-(D-Lysyl)piperidin-4-yl)thio)methyl)-8-methylquinazolin-4(3H)-oneDihydrochloride

The title compound was prepared from the compound of Example 13 and(R)-2,6-bis((tert-butoxycarbonyl)amino)hexanoic acid according to themethod described for Example 166. LCMS: [M+H]⁺ 418.2.

¹H NMR (400 MHz, CD₃OD) δ 8.14 (d, J=7.6 Hz, 1H), 7.83 (dd, J=3.2, 1.2Hz, 1H), 7.66-7.53 (m, 1H), 4.57-4.11 (m, 3H), 4.03-3.82 (m, 1H), 3.35(s, 2H), 3.22-2.90 (m, 3H), 2.70 (s, 3H), 2.32-2.09 (m, 2H), 1.96-1.42(m, 9H);

¹H NMR (400 MHz, DMSO-d₆) δ 12.5 (br s, 1H), 8.30 (s, 3H), 8.17 (s, 3H),7.93 (d, J=7.6 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H),4.41-4.27 (m, 1H)), 4.27-4.05 (m, 1H), 3.91-3.78 (1H, obscured by waterpeak), 3.76 (2H, obscured by water peak), 3.25-3.11 (m, 2H), 3.03-2.77(m, 1H), 2.80-2.66 (m, 2H), 2.51 (s, 3H), 2.13-1.99 (m, 2H), 1.73-1.61(m, 2H), 1.57-1.27 (m, 6H).

Example 173:8-Methyl-2-(((1-(3-(pyridin-2-yl)propanoyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of the compound of Example 13 (50 mg, 0.15 mmol, 1.0 eq),3-(pyridin-2-yl)propanoic acid (23 mg, 0.15 mmol, 1.0 eq) and Et₃N (46mg, 0.46 mmol, 3.0 eq) in DMF (3 mL) at RT under a N₂ atmosphere wasadded PyBOP (96 mg, 0.18 mmol, 1.2 eq) and the mixture was stirred for 4h. The mixture was diluted with water (40 mL), extracted with EtOAc (30mL×3) and the combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-TLC (DCM:MeOH, 10:1, v/v) to afford the title compound (16 mg, 25%)as a white solid. LCMS: [M+H]⁺ 423.2.

¹H NMR (400 MHz, CDCl₃) δ 10.2 (br s, 1H), 8.52 (d, J=4.8 Hz, 1H), 8.12(d, J=8.0 Hz, 1H), 7.71-7.63 (m, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.37 (t,J=7.6 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.18 (dd, J=7.6, 5.2 Hz, 1H),4.33 (m, 1H), 3.85 (m, 1H), 3.79 (s, 2H), 3.20-3.13 (m, 2H), 3.07 (m,1H), 2.96-2.77 (m, 4H), 2.58 (s, 3H), 2.03-1.95 (m, 2H), 1.56-1.43 (m,2H).

Example 174:8-Methyl-2-(((1-(methylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of Example 13 (100 mg, 0.31 mmol, 1.0 eq) and Et₃N (94 mg,0.93 mmol, 3.0 eq) in DCM (5 mL) at RT under a N₂ atmosphere was addedMsCl (42 mg, 0.37 mmol, 1.2 eq) and the mixture was stirred for 2 h. Themixture was diluted with water (20 mL), extracted with EtOAc (30 mL×3)and the combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by prep-TLC (DCM:MeOH,15:1, v/v) to afford the title compound (12 mg, 11%) as a white solid.LCMS: [M+H]⁺ 368.2;

¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz,1H), 7.42 (t, J=8.0 Hz, 1H), 3.98 (s, 2H), 3.65 (d, J=11.8 Hz, 2H),2.99-2.79 (m, 3H), 2.76 (s, 3H), 2.65 (s, 3H), 2.18-2.06 (m, 2H),1.80-1.70 (m, 2H).

Example 175:8-Methyl-2-(((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of Example 13 (50 mg, 0.15 mmol, 1.0 eq) and Et₃N (47 mg,0.47 mmol, 3.0 eq) in DMF (3 mL) at RT under a N₂ atmosphere was addedpyridine-2-sulfonyl chloride hydrochloride (41 mg, 0.23 mmol, 1.5 eq)and the mixture was stirred for 3 h. The mixture was diluted with water(20 mL) and extracted with EtOAc (30 mL×3) and the combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by prep-TLC (DCM:MeOH, 15:1, v/v) to afford thetitle compound (12 mg, 18%) as a white solid. LCMS: [M+H]⁺ 431.1.

¹H NMR (400 MHz, CD₃OD) δ 8.69 (d, J=4.8 Hz, 1H), 8.08-7.99 (m, 2H),7.94 (d, J=7.9 Hz, 1H), 7.67-7.59 (m, 2H), 7.38 (t, J=7.6 Hz, 1H),3.79-3.69 (m, 4H), 2.98-2.83 (m, 3H), 2.53 (s, 3H), 2.12-2.03 (m, 2H),1.68-1.55 (m, 2H).

Example 176:7-(Cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Step 1: tert-Butyl4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

To a solution of Int-B2 (44 mg, 0.17 mmol, 1.0 eq) and Int-A37 (50 mg,0.17 mmol, 1.0 eq) in THF (4 mL) was added 1 M NaOH (2 mL) and themixture was stirred at RT overnight under a N₂ atmosphere. The mixturewas diluted with water (5 mL) and extracted with EtOAc (20 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography(DCM:MeOH, 10:1, v/v) to afford the title compound (25 mg, 31%) as awhite solid. LCMS: [M+H]⁺ 477.2.

Step 2:7-(Cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

The title compound was prepared from tert-butyl4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate according to the method describedfor Example 48, step 2. LCMS: [M+H]⁺ 377.2.

¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (br s, 1H), 8.77 (br s, 1H), 6.53 (s,1H), 6.51 (d, J=14.0 Hz, 1H), 3.80-3.77 (m, 1H), 3.73 (s, 2H), 3.25-3.22(m, 2H), 3.17-3.11 (m, 1H), 2.94-2.86 (m, 2H), 2.16-2.13 (m, 2H),2.02-1.93 (m, 2H), 1.78-1.66 (m, 4H), 1.63-1.52 (m, 2H), 1.50-1.42 (m,2H).

Example 177:7-(Cyclobutylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Step 1: tert-Butyl4-(((7-(cyclobutylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

The title compound was prepared from Int-A38 and Int-B2 according to themethod described for Example 176, step 1. LCMS: [M+H]⁺ 463.2.

Step 2:7-(Cyclobutylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

The title compound was prepared from tert-butyl4-(((7-(cyclobutylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate according to the method describedfor Example 48, step 2. LCMS: [M+H]⁺ 363.2.

¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (br s, 1H), 8.88 (br s, 1H), 6.52 (s,1H), 6.47 (d, J=13.6 Hz, 1H), 3.96-3.88 (m, 1H), 3.77 (s, 2H), 3.24-3.15(m, 3H), 2.93-2.85 (m, 2H), 2.38-2.33 (m, 2H), 2.19-2.14 (m, 2H),1.92-1.85 (m, 2H), 1.78-1.61 (m, 4H).

Table 8 lists analytical data for the Examples.

TABLE 8 Example Analytical Data Example 2 LCMS: [M + H]⁺ 291.1; ¹H NMR(400 MHz, CDCl₃) δ 10.1 (s, 1H), 8.13 (dd, J = 8.0, 1.6 Hz, 1H), 7.62(d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 3.95 (dt,J = 11.6, 4.0Hz, 2H), 3.81 (s, 2H), 3.37 (td, J = 11.6, 2.4 Hz, 2H), 2.92 (tt, J =10.8, 4.0 Hz, 1H), 2.59 (s, 3H), 1.98-1.81 (m, 2H), 1.75-1.60 (m, 2H).Example 3 LCMS: [M + H]⁺ 291.1; ¹H NMR (400 MHz, CDCl₃) δ 9.88 (br s,1H), 8.08 (s, 1H), 7.59 (s, 2H), 3.93 (d, J = 11.6 Hz, 2H), 3.81 (s,2H), 3.36 (t, J = 11.2 Hz, 2H), 2.93-2.78 (m, 1H) 2.50 (s, 3H),1.94-1.85 (m, 2H), 1.67 (dd, J = 18.4, 8.0 Hz, 2H). Example 4 LCMS: [M +H]⁺ 307.1; ¹H NMR (400 MHz, CDCl₃) δ 9.80 (br s, 1H), 7.65 (s, 1H), 7.61(d, J = 9.2 Hz, 1H), 7.37 (d, J = 10.4 Hz, 1H), 3.93-3.89 (m, 5H), 3.80(s, 2H), 3.36 (t, J = 11.2 Hz, 2H), 2.92-2.79 (m, 1H), 1.95-1.85 (m,2H), 1.70-1.60 (m, 2H). Example 5 LCMS: [M + H]⁺ 311.1; ¹H NMR (400 MHz,DMSO-d₆) δ 12.6 (br s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 3.88-3.78 (m, 2H), 3.70 (s, 2H),3.33-3.17 (m. 2H), 3.20-3.12 (m, 1H), 2.00-1.90 (m, 2H), 1.50-1.40 (m,2H). Example 6 LCMS: [M + H]⁺ 307.1; ¹H NMR (400 MHz, DMSO-d₆) δ 12.3(br s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.34 (d,J = 7.8 Hz, 1H), 3.89 (s, 3H), 3.88- 3.78 (m, 2H), 3.68 (s, 2H),3.33-3.17 (m, 2H), 3.16-3.03 (m, 1H), 1.94-1.85 (m, 2H), 1.50-1.40 (m,2H). Example 7 LCMS: [M + H]⁺ 305.1; ¹H NMR (400 MHz, DMSO-d₆) δ 12.2(br s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.37 (t,J = 7.6 Hz, 1H), 4.00 (q, J = 7.2 Hz, 1H), 3.80-3.77 (m, 2H), 3.32-3.23(m, 2H), 3.12-3.00 (m, 1H), 2.51 (s, 3H), 1.90-1.82 (m, 1H), 1.79-1.69(m, 1H), 1.63 (d, J = 7.2 Hz, 3H), 1.43 (m, 2H). Example 8 LCMS: [M +H]⁺ 309.1; ¹H NMR (400 MHz, CD₃OD) δ 7.62 (dd, J = 8.0, 5.6 Hz, 1H),7.06 (dd, J = 10.8, 8.4 Hz, 1H), 3.92 (dt, J = 11.6, 3.6 Hz, 2H), 3.72(s, 2H), 3.41 (td, J = 11.2, 2.0 Hz, 2H), 3.13-3.05 (m, 1H), 2.51 (s,3H), 2.05-1.95 (m, 2H), 1.71-1.61 (m, 2H). Example 9 LCMS: [M + H]⁺291.1; ¹H NMR (400 MHz, CDCl₃) δ 10.1 (s, 1H), 7.60 (t, J = 7.6 Hz, 1H),7.50 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 3.93 (dt, J = 12.0,3.6 Hz, 2H), 3.76 (s, 2H), 3.37 (t, J = 11.2 Hz, 2H), 2.93-2.89 (m, 4H),1.91 (d, J = 12.4 Hz, 2H), 1.71-1.61 (m, 2H). Example 10 LCMS: [M + H]⁺367.1; ¹H NMR (400 MHz, CDCl₃) δ 9.80 (br s, 1H), 8.17 (d, J = 8.0 Hz,1H), 7.58 (d, J = 7.2 Hz, 1H), 7.44-7.37 (m, 1H), 7.25-7.12 (m, 5H),4.40 (s, 2H), 3.94-3.84 (m, 2H), 3.78 (s, 2H), 3.28 (t, J = 11.2 Hz,2H), 2.89- 2.77 (m, 1H), 1.91-1.80 (m, 2H), 1.70-1.60 (m, 2H). Example11 LCMS: [M + H]⁺ 367.1; ¹H NMR (400 MHz, CDCl₃) δ 9.75 (br s, 1H), 8.19(d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.30-7.14 (m, 6H), 4.11 (s, 2H), 3.93(dt, J = 11.8, 3.6 Hz, 2H), 3.77 (s, 2H), 3.36 (t, J = 11.4 Hz, 2H),2.80 (m, 1H), 1.83 (d, J = 13.2 Hz, 2H), 1.74-1.60 (m, 2H). Example 29LCMS: [M + H]⁺ 369.1; ¹H NMR (400 MHz, DMSO-d₆) δ 12.3 (s, 1H), 8.08 (d,J = 8.8 Hz, 1H), 7.53-7.45 (m, 2H), 7.29 (td, J = 7.3, 1.1 Hz, 1H),7.22-7.16 (m, 2H), 7.13 (dd, J = 8.8, 2.4 Hz, 1H), 6.91 (d, J = 2.4 Hz,1H), 3.79 (dt, J = 11.6, 4.0 Hz, 2H), 3.63 (s, 2H), 3.28 (dd, J = 11.2,2.4 Hz, 2H), 3.08- 2.96 (m, 1H), 1.86 (d, J = 13.2 Hz, 2H), 1.47-1.37(m, 2H). Example 30 LCMS: [M + H]⁺ 295.1; ¹H NMR (400 MHz, DMSO-d₆) δ12.4 (s, 1H), 8.14 (dd, J = 8.8, 6.4 Hz, 1H), 7.47-7.30 (m, 2H), 3.80(dt, J = 11.6, 3.6 Hz, 2H), 3.67 (s, 2H), 3.37-3.26 (m, 2H), 3.06 (tt, J= 10.8, 4.0 Hz, 1H), 1.88 (dd, J = 13.2, 3.6 Hz, 2H), 1.51-1.40 (m, 2H).Example 31 LCMS: [M + H]⁺ 307.1; ¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (s,1H), 7.98 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.0 Hz, 2H), 3.88 (s, 3H),3.83-3.76 (m, 2H), 3.65 (s, 2H), 3.30-3.00 (m, 2H), 3.05 (td, J = 10.8,5.2 Hz, 1H), 1.93-1.84 (m, 2H), 1.52-1.38 (m, 2H). Example 32 LCMS: [M +H]⁺ 304.1; ¹H NMR (400 MHz, CDCl₃) δ 14.1 (br s, 1H), 8.10 (d, J = 7.2Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 4.07 (d, J= 15.2 Hz, 1H), 3.82-3.73 (m, 1H), 3.43 (d, J = 15.2 Hz, 1H), 3.05 (dd,J = 15.2, 3.2 Hz, 1H), 2.92 (dd, J = 15.2, 3.2 Hz, 1H), 2.76-2.68 (m,1H), 2.57 (s, 3H), 2.43 (s, 3H), 2.35 (dd, J = 16.4, 9.2 Hz, 1H),1.99-1.76 (m, 4H). Example 33 LCMS: [M + H]⁺ 309.1; ¹H NMR (400 MHz,CDCl₃) δ 10.5 (s, 1H), 8.14 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 8.8 Hz,1H), 3.96 (d, J = 12.0 Hz, 2H), 3.81 (s, 2H), 3.38 (t, J = 11.2 Hz, 2H),3.00-2.82 (m, 1H), 2.49 (s, 3H), 1.94 (d, J = 13.2 Hz, 2H), 1.72-1.62(m, 2H). Example 34 LCMS: [M + H]⁺ 325.1; ¹H NMR (400 MHz, CDCl₃) δ 9.77(s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 3.95 (d, J= 12.0 Hz, 2H), 3.76 (s, 2H), 3.37 (t, J = 11.2 Hz, 2H), 2.95-2.83 (m,1H), 2.52 (s, 3H), 1.94-1.90 (m, 2H), 1.74-1.60 (m, 2H). Example 35LCMS: [M + H]⁺ 359.1; ¹H NMR (400 MHz, CDCl₃) δ 10.8 (s, 1H), 7.77-7.67(m, 2H), 3.98- 3.95 (m, 2H), 3.80 (s, 2H), 3.57-3.30 (m, 2H), 3.01-2.94(m, 1H), 2.63 (s, 3H), 1.97-1.94 (m, 2H), 1.70-1.67 (m, 2H). Example 36LCMS: [M + H]⁺ 278.1^(;) ¹H NMR (400 MHz, DMSO-d₆) δ 12.6 (s, 1H), 8.76(s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.78 (dd,J = 8.4, 4.2 Hz, 1H), 3.80(d, J = 11.6 Hz, 2H), 3.70 (s, 2H), 3.31-3.28 (m, 2H), 3.07 (t, J = 10.4Hz, 1H), 1.88 (d, J = 12.8 Hz, 2H), 1.45 (q, J = 12.0, 11.0 Hz, 2H).Example 37 LCMS: [M + H]⁺ 278.1; ¹H NMR (400 MHz, CD₃OD) δ 8.99 (s, 1H),8.62 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 5.2 Hz, 1H), 3.91 (dt, J = 11.6,3.6 Hz, 2H), 3.77 (s, 2H), 3.43 (dt, J = 11.2, 2.4 Hz, 2H), 3.09-3.02(m, 1H), 1.97 (d, J = 13.6 Hz, 2H), 1.63-1.54 (m, 2H). Example 38 LCMS:[M + H]⁺ 367.1; ¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J = 7.4 Hz, 1H), 7.62(d, J = 6.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.35-7.26 (m, 5H), 4.37(s, 2H), 4.35- 4.27 (m, 1H), 3.84 (s, 2H), 3.58-3.52 (m, 1H), 2.62 (s,3H), 2.47- 2.40 (m, 2H), 2.31-2.17 (m, 2H). Example 39 LCMS: [M + H]⁺263.1; ¹H NMR (400 MHz, CD₃OD) δ 8.03 (dd, J = 8.0, 1.6 Hz, 1H), 7.67(d, J = 7.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 4.89 (t, J = 7.2 Hz, 2H),4.42 (t, J = 6.4 Hz, 2H), 4.36-4.30 (m, 1H), 3.73 (s, 2H), 2.60 (s, 3H).Example 40 LCMS: [M + H]⁺ 278.1; ¹H NMR (400 MHz, CD₃OD) δ 8.83 (s, 1H),8.67 (d, J = 6.0 Hz, 1H), 8.19 (d, J = 6.0 Hz, 1H), 4.00-3.90 (m, 2H),3.56 (s, 2H), 3.46 (td, J = 11.2, 2.4 Hz, 2H), 3.17-3.04 (m, 1H),2.07-1.95 (m, 2H), 1.69-1.55 (m, 2H). Example 41 LCMS: [M + H]⁺ 292.1;¹H NMR (400 MHz, CD₃OD) δ 8.56 (d, J = 4.4 Hz, 1H), 7.69 (d, J = 4.4 Hz,1H), 3.92 (dt, J = 11.8, 3.6 Hz, 2H), 3.78 (s, 2H), 3.41 (td, J = 11.6,2.4 Hz, 2H), 3.13-3.06 (m, 1H), 2.64 (s, 3H), 2.06-1.88 (m, 2H),1.64-1.55 (m, 2H). Example 42 LCMS: [M + H]⁺ 292.1; ¹H NMR (400 MHz,CD₃OD) δ 8.44 (d, J = 5.4 Hz, 1H), 7.90 (d, J = 5.4 Hz, 1H), 3.92 (dt, J= 11.8, 3.6 Hz, 2H), 3.77 (s, 2H), 3.42 (td, J = 11.2, 2.4 Hz, 2H),3.13-3.06 (m, 1H), 2.82 (s, 3H), 2.06-1.94 (m, 2H), 1.65-1.55 (m, 2H).Example 43 LCMS: [M + H]⁺ 278.1; ¹H NMR (400 MHz, CD₃OD) δ 8.95 (s, 1H),8.71 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (dd, J = 8.0, 4.8 Hz, 1H), 3.91(dt, J = 11.6, 3.6 Hz, 2H), 3.72 (s, 2H), 3.43 (td, J = 11.2, 2.4 Hz,2H), 3.16-3.09 (m, 1H), 2.02-1.91 (m, 2H), 1.63-1.54 (m, 2H). Example 44LCMS: [M + H]⁺ 325.1; ¹H NMR (400 MHz, CD₃OD) δ 7.98-7.95 (m, 1H),7.67-7.62 (m, 1H), 3.95-3.88 (m, 2H), 3.74 (s, 2H), 3.45-3.36 (m, 2H),3.15-3.01 (m, 1H), 2.56 (s, 3H), 2.03-1.95 (m, 2H), 1.65-1.54 (m, 2H).Example 45 LCMS: [M + H]⁺ 313.1; ¹H NMR (400 MHz, DMSO-d₆) δ 12.6 (s,1H), 8.02-7.84 (m, 1H), 7.64-7.42 (m, 1H), 3.87-3.78 (m, 2H), 3.71 (s,2H), 3.34-3.25 (m, 2H), 3.15-3.02 (m, 1H), 1.95-1.85 (m, 2H), 1.53-1.38(m, 2H). Example 81 LCMS: [M + H]⁺ 369.1; ¹H NMR (400 MHz, DMSO-d₆) δ9.76 (s, 1H), 8.34-8.20 (m, 2H), 7.96 (d, J = 8.8 Hz, 1H), 7.74-7.56 (m,2H), 7.04-6.85 (m, 2H), 3.81 (d, J = 11.2 Hz, 2H), 3.69 (d, J = 6.0 Hz,2H), 3.33 (q, J = 11.2 Hz, 2H), 3.08 (t, J = 10.8 Hz, 1H), 1.90 (d, J =13.2 Hz, 2H), 1.46 (q, J = 11.6, 10.0 Hz, 2H). Example 82 LCMS: [M + H]⁺398.2; ¹H NMR (400 MHz, CD₃OD) δ 7.95 (d, J = 8.8 Hz, 1H), 7.20 (d, J =8.4 Hz, 2H), 7.03-6.91 (m, 4H), 3.89 (dt, J = 11.6, 4.0 Hz, 2H), 3.81(s, 3H), 3.70 (d, J = 6.0 Hz, 2H), 3.42 (td, J = 11.2, 2.4 Hz, 2H),3.05- 2.98 (m, 1H), 1.93 (d, J = 13.6 Hz, 2H), 1.61-1.52 (m, 2H).Example 83 LCMS: [M + H]⁺ 398.2; ¹H NMR (400 MHz, DMSO-d₆) δ 11.9 (s,1H), 8.88 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H),7.15-7.04 (m, 2H), 6.85-6.77 (m, 1H), 6.74 (t, J = 2.4 Hz, 1H), 6.60(dd, J = 8.0, 2.4 Hz, 1H), 3.80 (d, J = 12.0 Hz, 2H), 3.75 (s, 3H), 3.61(s, 2H), 3.30-3.27 (m, 2H), 3.09-3.00 (m, 1H), 1.88 (d, J = 12.4 Hz,2H), 1.49-1.38 (m, 2H). Example 84 LCMS: [M + H]⁺ 398.2; ¹H NMR (400MHz, DMSO-d₆) δ 8.61 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.30 (dd, J =7.6, 1.6 Hz, 1H), 7.21-7.13 (m, 2H), 7.05 (dd, J = 8.8, 2.4 Hz, 1H),6.99 (td, J = 7.6, 1.6 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 3.85-3.75 (m,7H), 3.31 (m, 2H), 3.13-3.07 (m, 1H), 1.93-1.84 (m, 2H), 1.49-1.36 (m,2H). Example 85 LCMS: [M + H]⁺ 370.1; ¹H NMR (400 MHz, DMSO-d₆) δ 12.1(s, 1H), 10.0 (s, 1H), 8.34 (s, 1H), 8.27 (br s, 1H), 8.19 (d, J = 2.0Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.61 (dd, J= 8.8, 2.0 Hz, 1H), 3.92-3.80 (m, 2H), 3.66 (s, 2H), 3.37-3.29 (m, 2H),3.09-3.04 (m, 1H), 1.90 (d, J = 12.8 Hz, 2H), 1.50-1.41 (m, 2H). Example86 LCMS: [M + H]⁺ 369.1; ¹H NMR (400 MHz, CD₃OD) δ 8.32-8.25 (m, 2H),8.14 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.8,2.4 Hz, 1H), 7.24- 7.16 (m, 2H), 3.90 (dt, J = 11.6, 3.6 Hz, 2H), 3.73(s, 2H), 3.43 (td, J = 11.2, 2.4 Hz, 2H), 3.08-2.99 (m, 1H), 1.96 (d, J= 13.2 Hz, 2H), 1.59 (m, 2H). Example 87 LCMS: [M + H]⁺ 370.1; ¹H NMR(400 MHz, DMSO-d₆) δ 12.0 (s, 1H), 9.15 (s, 1H), 8.82 (s, 1H), 8.73 (s,2H), 7.97 (d, J = 8.8 Hz, 1H), 7.19 (dd, J = 8.8, 2.0 Hz, 1H), 7.10 (s,1H), 3.82-3.80 (m, 2H), 3.63 (s, 2H), 3.32-3.28 (m, 2H), 3.08-3.03 (m,1H), 1.88 (d, J = 13.2 Hz, 2H), 1.49-1.42 (m, 2H). Example 88 LCMS: [M +H]⁺ 372.1; ¹H NMR (400 MHz, CD₃OD) δ 8.01 (d, J = 8.8 Hz, 1H), 7.10-7.05(m, 1H), 7.04-6.99 (m, 2H), 6.89 (d, J = 1.6 Hz, 1H), 3.92-3.86 (m, 2H),3.68 (s, 2H), 3.70 (s, 3H), 3.45-3.37 (m, 2H), 3.06-2.95 (m, 1H),1.97-1.89 (m, 2H), 1.62-1.50 (m, 2H). Example 89 LCMS: [M + H]⁺ 375.1;¹H NMR (400 MHz, CD₃OD) δ 8.23 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 8.8 Hz,1H), 7.51 (dd, J = 8.8, 2.4 Hz, 1H), 7.36 (d, J = 3.6 Hz, 1H), 6.96 (d,J = 3.6 Hz, 1H), 3.93-3.88 (m, 2H), 3.75 (s, 2H), 3.47-3.41 (m, 2H),3.09-3.02 (m, 1H), 1.98-1.94 (m, 2H), 1.64-1.54 (m, 2H). Example 90LCMS: [M + H]⁺ 383.2; ¹H NMR (400 MHz, DMSO-d₆) δ 11.9 (s, 1H), 8.40 (d,J = 8.0 Hz, 1H), 8.26 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H),7.67 (d, J = 8.0 Hz, 1H), 7.28-7.25 (m, 1H), 6.95 (d, J = 12.4 Hz, 1H),6.69 (s, 1H), 3.82- 3.76 (m, 2H), 3.59 (s, 2H), 3.30-3.26 (m, 2H),3.06-2.97 (m, 1H), 2.42 (s, 3H), 1.87 (d, J = 12.8 Hz, 2H), 1.49-1.38(m, 2H). Example 91 LCMS: [M + H]⁺ 383.2; ¹H NMR (400 MHz, DMSO-d₆) δ11.9 (s, 1H), 8.45 (d, J = 8.0 Hz, 2H), 8.29 (d, J = 4.0 Hz, 1H), 7.87(d, J = 8.0 Hz, 1H), 7.35 (d, J = 4.0 Hz, 1H), 6.91 (dd, J = 8.0 Hz,1H), 6.59 (d, J = 4.0 Hz, 1H), 3.83-3.76 (m, 2H), 3.58 (s, 2H), 3.28 (d,J = 4.0 Hz, 2H), 3.06-2.97 (m, 1H), 2.21 (s, 3H), 1.87 (d, J = 12.0 Hz,2H), 1.49-1.37 (m, 2H). Example 92 LCMS: [M + H]⁺ 383.2; ¹H NMR (400MHz, DMSO-d₆) δ 12.0 (s, 1H), 8.98 (s, 1H), 8.28 (s, 1H), 8.08 (s, 1H),7.93 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 7.13 (dd, J = 8.8, 2.0 Hz, 1H),7.09-7.01 (m, 1H), 3.86-3.75 (m, 2H), 3.62 (s, 2H), 3.30-3.24 (m, 2H),3.12-3.01 (m, 1H), 2.31 (s, 3H), 1.89 (d, J = 11.8 Hz, 2H), 1.50-1.36(m, 2H). Example 109 LCMS: [M + H]⁺ 320.1; ¹H NMR (400 MHz, DMSO-d₆) δ11.8 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 6.90 (dd, J = 8.8, 1.6 Hz, 1H),6.63 (d, J = 1.6 Hz, 1H), 3.81 (dt, J = 11.6, 3.6 Hz, 2H), 3.60 (s, 2H),3.37-3.32 (m, 1H), 3.31-3.26 (m, 1H), 3.03 (s, 6H), 3.02-2.99 (m, 1H),1.88 (d, J = 12.4 Hz, 2H), 1.52- 1.37 (m, 2H). Example 110 LCMS: [M +H]⁺ 306.1; ¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 7.74 (d, J = 8.8Hz, 1H), 6.71 (dd, J = 8.8, 2.0 Hz, 1H), 6.65 (d, J = 4.8 Hz, 1H), 6.45(d, J = 2.0 Hz, 1H), 3.87-3.76 (m, 2H), 3.59 (s, 2H), 3.37-3.33 (m, 1H),3.29 (d, J = 2.0 Hz, 1H), 3.11-2.99 (m, 1H), 2.76 (d, J = 4.8 Hz, 3H),1.94- 1.83 (m, 2H), 1.51-1.39 (m, 2H). Example 111 LCMS: [M + H]⁺ 362.2;¹H NMR (400 MHz, DMSO-d₆) δ 11.9 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.15(dd, J = 8.8, 2.4 Hz, 1H), 6.93-6.88 (m, 1H), 3.87-3.77 (m, 2H),3.78-3.71 (m, 4H), 3.62 (s, 2H), 3.11-2.99 (m, 1H), 2.07-1.94 (m, 1H),1.93-1.84 (m, 2H), 1.52-1.38 (m, 2H), 1.35-1.14 (m, 5H). Example 112LCMS: [M + H]⁺ 375.2; ¹H NMR (400 MHz, DMSO-d₆) δ 11.9 (s, 1H), 7.86 (d,J = 8.8 Hz, 1H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz,1H), 3.81 (dt, J = 11.6, 3.6 Hz, 2H), 3.61 (s, 2H), 3.37-3.32 (m, 5H),3.32-3.27 (m, 1H), 3.10-3.00 (m, 1H), 2.44 (t, J = 5.0 Hz, 4H), 2.22 (s,3H), 1.89 (d, J = 12.8 Hz, 2H), 1.52-1.39 (m, 2H). Example 113 LCMS:[M + H]⁺ 389.2; ¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 7.75 (d, J =8.8 Hz, 1H), 6.76 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 6.62 (d, J = 7.6 Hz,1H), 6.57 (s, 1H), 3.81 (d, J = 11.2 Hz, 2H), 3.59 (s, 2H), 3.56-3.47(m, 1H), 3.30-2.99 (m, 10H), 2.07-1.98 (m, 2H), 1.92-1.84 (m, 2H),1.67-1.55 (m, 2H), 1.49-1.40 (m, 2H). Example 114 LCMS: [M + H]⁺ 376.2;¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H),6.77-6.74 (m, 1H), 6.56-6.54 (m, 2H), 3.88-3.79 (m, 4H), 3.58 (s, 3H),3.45 (t, J = 10.4 Hz, 2H), 3.32-3.28 (m, 2H), 3.07-2.99 (m, 1H), 1.88(d, J = 12.8 Hz, 4H), 1.49-1.36 (m, 4H). Example 115 LCMS: [M + H]⁺360.2; ¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 7.72 (d, J = 8.8 Hz,1H), 6.74-6.71 (m, 1H), 6.60 (d, J = 8.8 Hz, 1H), 6.48 (d, J = 1.6 Hz,1H), 3.82-3.76 (m, 3H), 3.59 (s, 2H), 3.32-3.28 (m, 2H), 3.00-3.07 (m,1H), 1.98-1.87 (m, 4H), 1.69-1.55 (m, 4H), 1.51-1.49 (m, 4H). Example116 LCMS: [M + H]⁺ 334.2; ¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H),7.76-7.71 (m, 1H), 6.71 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 6.50-6.43 (m, 2H),3.85-3.77 (m, 2H), 3.70-3.61 (m, 1H), 3.59 (s, 2H), 3.36-3.26 (m, 2H),3.09- 3.00 (m, 1H), 1.93-1.83 (m, 2H), 1.50-1.38 (m, 2H), 1.17 (d, J =6.4 Hz, 6H). Example 117 LCMS: [M + H]⁺ 383.2; ¹H NMR (400 MHz, DMSO-d₆)δ 11.7 (s, 1H), 8.51 (d, J = 6.0 Hz, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.36(d, J = 5.6 Hz, 2H), 7.32 (t, J = 6.0 Hz, 1H), 6.81 (dd, J = 8.8, 2.4Hz, 1H), 6.40 (d, J = 2.0 Hz, 1H), 4.45 (d, J = 6.0 Hz, 2H), 3.79 (dt, J= 11.6, 3.6 Hz, 2H), 3.55 (s, 2H), 3.25 (td, J = 11.6, 2.4 Hz, 2H),3.02-2.95 (m, 1H), 1.85 (d,J = 12.4 Hz, 2H), 1.47- 1.35 (m, 2H). Example118 LCMS: [M + H]⁺ 383.2; ¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 8.54(d, J = 4.8 Hz, 1H), 7.72-7.78 (m, 2H), 7.36-7.25 (m, 3H), 6.83 (dd, J =8.8, 2.0 Hz, 1H), 6.44 (d, J = 4.0 Hz, 1H), 4.47 (d, J = 6.8 Hz, 2H),3.76-3.83 (m, 2H), 3.56 (s, 2H), 3.22-3.30 (m, 2H), 3.03-2.95 (m, 1H),1.85 (d, J = 12.0 Hz, 2H), 1.46-1.36 (m, 2H). Example 119 LCMS: [M + H]⁺382.2; ¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 7.73 (d, J = 8.0 Hz,1H), 7.31-7.37 (m, 4H), 7.21-7.26 (m, 2H), 6.79 (d, J = 12.0 Hz, 1H),6.45 (d, J = 2.4 Hz, 1H), 4.37 (d, J = 4.0 Hz, 2H), 3.76-3.81 (m, 2H),3.55 (s, 2H), 3.26 (t, J = 9.2 Hz, 2H), 2.95-3.05 (m, 1H), 1.85 (d, J =12.0 Hz, 2H), 1.35-1.47 (m, 2H). Example 120 LCMS: [M + H]⁺ 396.2; ¹HNMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.38(d, J = 4.0 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H),7.14 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.32 (s, 1H),4.55-4.63 (m, 1H), 3.75-3.81 (m, 2H), 3.52 (s, 2H), 3.20-3.27 (m, 2H),2.93-3.00 (m, 1H), 1.78-1.87 (m, 2H), 1.45 (d, J = 8.0 Hz, 3H),1.34-1.40 (m, 2H). Example 121 LCMS: [M + H]⁺ 362.1; ¹H NMR (400 MHz,DMSO-d₆) δ 11.7 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 6.4 Hz,1H), 6.76 (dd, J = 8.8, 2.0 Hz, 1H), 6.51 (d, J = 2.0 Hz, 1H), 4.10 (s,1H), 3.91-3.86 (m, 1H), 3.81 (dt, J = 7.6, 5.6 Hz, 3H), 3.74 (td, J =8.0, 5.6 Hz, 1H), 3.62-3.56 (m, 3H), 3.30 (d, J = 11.6 Hz, 2H),3.09-3.00 (m, 1H), 2.22 (dq, J = 14.9, 7.5 Hz, 1H), 1.88 (d, J = 12.4Hz, 2H), 1.80 (dd, J = 16.0, 12.6 Hz, 1H), 1.44 (qd, J = 10.9, 4.2 Hz,2H). Example 122 LCMS: [M + H]⁺ 346.2; ¹H NMR (400 MHz, DMSO-d₆) δ 11.7(s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 6.4 Hz, 1H), 6.68 (dd, J= 8.8, 2.0 Hz, 1H), 6.40 (d, J = 2.0 Hz, 1H), 3.93 (d, J = 7.2 Hz, 1H),3.80 (dd, J = 13.2, 9.8 Hz, 2H), 3.58 (s, 2H), 3.35 (d, J = 6.8 Hz, 1H),3.28 (d, J = 7.2 Hz, 1H), 3.08-2.98 (m, 1H), 2.41-2.31 (m, 2H),1.95-1.81 (m, 4H), 1.79-1.71 (m, 2H), 1.51-1.38 (m, 2H) Example 123LCMS: [M + H]⁺ 383.2; ¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (br s, 1H), 8.60(d, J = 1.6 Hz, 1H), 8.46 (dd, J = 4.4, 0.8 Hz, 1H), 7.75 (d, J = 8.8Hz, 2H), 7.36 (m, 1H), 7.24 (t, J = 6.0 Hz, 1H), 6.81 (dd, J = 8.8, 2.0Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 3.82-3.76(m, 2H), 3.56 (s, 2H), 3.24-3.31 (m, 2H), 3.03-2.96 (m, 1H), 1.86 (d, J= 12.0 Hz, 2H), 1.46-1.36 (m, 2H). Example 124 LCMS: [M + H]⁺ 332.1; ¹HNMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 6.98(s, 1H), 6.78 (dd, J = 8.8, 2.0 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H),3.85-3.79 (m, 2H), 3.60 (s, 2H), 3.33-3.29 (m, 2H), 3.07-3.02 (m, 1H),2.43 (br s, 1H), 1.91-1.87 (m, 2H), 1.49-1.41 (m, 2H), 0.78- 0.74 (m,2H), 0.44-0.40 (m, 2H). Example 125 LCMS: [M + H]⁺ 388.2; ¹H NMR (400MHz, CD₃OD) δ 7.96 (d, J = 9.2 Hz, 1H), 7.03 (dd, J = 9.2, 2.4 Hz, 1H),6.78 (d, J = 2.4 Hz, 1H), 3.92-3.87 (m, 2H), 3.85- 3.78 (m, 1H), 3.69(s, 2H), 3.43 (td, J = 11.6, 2.0 Hz, 2H), 3.07-2.97 (m, 1H), 2.93 (s,3H), 1.96-1.88 (m, 4H), 1.81-1.72 (m, 3H), 1.67- 1.44 (m, 6H), 1.27-1.21(m, 1H). Example 139 LCMS: [M + H]⁺ 437.2; ¹H NMR (400 MHz, CD₃OD) δ8.03 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 3H), 7.41 (d, J = 8.0 Hz,3H), 4.24 (s, 2H), 3.79 (s, 2H), 3.51 (d, J = 13.6 Hz, 2H), 3.33 (m,1H), 2.99 (t, J = 13.6 Hz, 2H), 2.58 (s, 3H), 2.38 (d, J = 14.4 Hz, 2H),2.14 (s, 3H), 1.73 (m, 2H). Example 140 LCMS: [M + H]⁺ 423.2; ¹H NMR(400 MHz, CD₃OD) δ 7.88 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H),7.30 (d, J = 8.4 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.00 (d, J = 8.0 Hz,2H), 4.01 (s, 2H), 3.38 (s, 2H), 3.18-3.13 (m, 3H), 2.96 (s, 6H),2.91-2.80 (m, 2H), 2.44 (s, 3H), 2.27-2.14 (m, 2H), 1.70-1.55 (m, 2H).Example 141 LCMS: [M + H]⁺ 405.2; ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J =8.0 Hz, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.67 (d, J = 7.2 Hz, 1H), 7.56(d, J = 8.0 Hz, 2H), 7.43 (t, J = 7.6 Hz, 1H), 4.24 (s, 2H), 3.84 (m,2H), 3.62 (m, 1H), 3.42 (s, 2H), 3.11 (s, 1H), 2.81 (m, 1H), 2.57 (s,3H), 2.41-2.23 (m, 2H), 2.09-2.01 (m, 2H). Example 142 LCMS: [M + H]⁺370.2; ¹H NMR (400 MHz, DMSO-d₆) δ 12.4 (s, 1H), 9.93 (s, 1H), 7.93 (d,J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.37 (t, J =7.6 Hz, 1H), 6.41 (s, 1H), 4.29 (s, 2H), 3.71 (s, 2H), 3.45 (d, J = 13.1Hz, 2H), 3.31-3.11 (m, 1H), 2.98 (m, 2H), 2.50 (3H, obscured by solventpeak), 2.24 (d, J = 14.0 Hz, 2H), 1.70-1.64 (m, 2H). Example 143 LCMS:[M + H]⁺ 434.2; ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J = 8.0 Hz, 1H), 7.84(d, J = 8.4 Hz, 1H), 7.64 (dd, J = 14.0, 8.0 Hz, 2H), 7.50 (t, J = 8.0Hz, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 4.66 (s,2H), 4.12 (s, 3H), 3.79 (s, 2H), 3.69 (d, J = 12.4 Hz, 2H), 3.19-2.97(m, 3H), 2.55 (s, 3H), 2.41-2.36 (m, 2H), 1.72 (m, 2H). Example 144LCMS: [M + H]⁺ 398.2; ¹H NMR (400 MHz, DMSO-d₆) δ 12.3 (s, 1H), 9.43 (s,1H), 7.93 (d, J = 8.0 Hz, 1H), 7.76-7.56 (m, 2H), 7.37 (t, J = 7.6 Hz,1H), 4.08 (s, 2H), 3.76 (s, 3H), 3.71 (s, 2H), 3.42 (d, J = 11.6 Hz,2H), 3.26-3.05 (m, 1H), 2.98-2.85 (m, 2H), 2.50 (3H obscured by solventpek), 2.25 (m, 2H), 2.15 (s, 3H), 1.67-1.57 (m, 2H). Example 145 LCMS:[M + H]⁺ 395.2; ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J = 8.0 Hz, 1H), 7.77(t, J = 8.0 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H),7.32 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 4.39 (s, 2H), 3.81(s, 2H), 3.55 (d, J = 12.4 Hz, 2H), 3.19 (m, 3H), 2.58 (s, 6H),2.38-2.34 (m, 2H), 1.97-1.91 (m, 2H). Example 146 LCMS: [M + H]⁺ 395.2;¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.68(t, J = 9.2 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.33 (s, 1H), 4.49 (s,2H), 3.83 (s, 2H), 3.63 (d, J = 12.8 Hz, 2H), 3.24 (m, 3H), 2.60 (s,3H), 2.41-2.37 (m, 2H), 2.32 (s, 3H), 2.06-2.00 (m, 2H). Example 147LCMS: [M + H]⁺ 394.2; ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J = 8.0 Hz,1H), 7.67 (d, J = 7.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.36-7.31 (m,2H), 7.29-7.24 (m, 3H), 3.83 (s, 2H), 3.69 (d, J = 12.6 Hz, 2H), 3.49(m, 1H), 3.42- 3.33 (m, 2H), 3.10-2.99 (m, 4H), 2.59 (s, 3H), 2.43-2.39(m, 2H), 1.84-1.74 (m, 2H). Example 148 LCMS: [M + H]⁺ 434.2; ¹H NMR(400 MHz, CD₃OD) δ 8.05 (s, 1H), 8.02 (dd, J = 8.0, 1.6 Hz, 1H), 7.86(d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.38 (t, J= 7.6 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.45 (s, 2H), 4.09 (s, 3H),3.56 (m, 2H), 3.37 (s, 2H), 3.06 (m, 3H), 2.57 (s, 3H), 2.38-2.35 (m,2H), 1.82-1.72 (m, 2H). Example 149 LCMS: [M + H]⁺ 384.2; ¹H NMR (400MHz, CD₃OD) δ 8.03 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 9.6 Hz, 2H), 7.39(t, J = 7.6 Hz, 1H), 4.18 (s, 2H), 3.63-3.50 (m, 2H), 3.49-3.23 (m, 2H),3.04-2.89 (m, 3H), 2.58 (s, 3H), 2.38 (d, J = 14.2 Hz, 2H), 2.32 (s,3H), 1.81-1.69 (m, 2H). Example 150 LCMS: [M + H]⁺ 437.2; ¹H NMR (400MHz, CD₃OD) δ 7.92 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J = 7.2Hz, 1H), 7.36-7.28 (m, 3H), 7.09 (d, J = 6.8 Hz, 1H), 4.21 (s, 2H),3.44-3.41 (m, 2H), 3.25 (s, 2H), 2.95-2.89 (m, 3H), 2.46 (s, 3H), 2.27(d, J = 14.4 Hz, 2H), 2.04 (s, 3H), 1.69-1.63 (m, 2H). Example 151 LCMS:[M + H]⁺ 420.2; ¹H NMR (400 MHz, CD₃OD) δ 9.38 (s, 1H), 8.44 (d, J = 6.8 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 7.2 Hz,1H), 7.39 (t, J = 7.6 Hz, 1H), 4.65 (s, 2H), 3.79 (s, 2H), 3.72-3.36 (m,3H), 3.05 (m, 2H), 2.58 (s, 3H), 2.37 (m, 2H), 1.78 (m, 2H). Example 152LCMS: [M + H]⁺ 420.2; ¹H NMR (400 MHz, CD₃OD) δ 8.96 (d, J = 6.8 Hz,1H), 8.29 (s, 1H), 8.06-7.97 (m, 3H), 7.67 (d, J = 7.2 Hz, 1H), 7.57 (t,J = 6.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 3.62-3.59 (m, 2H), 3.31 (4H,obscured by solvent peak), 3.18 (m, 3H), 2.59 (s, 3H), 2.31 (d, J = 16.4Hz, 2H), 1.92-1.88 (m, 2H). Example 153 LCMS: [M + H]⁺ 460.2; ¹H NMR(400 MHz, CD₃OD) δ 8.94 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H),7.67 (d, J = 7.2 Hz, 1H), 7.46-7.33 (m, 6H), 5.55 (s, 2H), 4.46 (s, 2H),3.47 (m, 2H), 3.31 (2H obscured by solvent peak), 3.13- 3.04 (m, 3H),2.59 (s, 3H), 2.31 (m, 2H), 1.94-1.87 (m, 2H). Example 154 LCMS: [M +H]⁺ 460.2; ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J = 8.0 Hz, 1H), 7.87 (d,J = 4.0 Hz, 1H), 7.70-7.61 (m, 2H), 7.43-7.23 (m, 6H), 5.36 (s, 2H),4.22 (s, 2H), 3.51-3.48 (m, 2H), 3.31 (2H, obscured by solvent peak),3.05-2.90 (m, 3H), 2.57 (s, 3H), 2.38 (m, 2H), 1.70 (m, 2H). Example 155LCMS: [M + H]⁺ 435.2; ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J = 7.6 Hz,1H), 7.67 (d, J = 7.2 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.49 (d, J =7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.20(t, J = 7.6 Hz, 1H), 5.12 (s, 2H), 4.37 (s, 2H), 3.54 (m, 2H), 3.35 (s,2H), 3.07-3.04 (m, 3H), 2.59 (s, 3H), 2.38 (m, 2H), 1.77-1.74 (m, 2H).Example 156 LCMS: [M + H]⁺ 435.2; ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J =8.0 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.43-7.30 (m, 2H), 7.10 (d, J =7.6 Hz, 1H), 7.02 (s, 1H), 4.29 (s, 2H), 3.61-3.46 (m, 3H), 3.01 (m,3H), 2.57 (s, 3H), 2.37 (m, 2H), 1.77 (m, 2H). Note: 3H obscured bywater and/or solvent peak. Example 157 LCMS: [M + H]⁺ 411.2; ¹H NMR (400MHz, CD₃OD) δ 8.27 (d, J = 2.4 Hz, 1H), 8.03 (dd, J = 8.0, 1.6 Hz, 1H),7.66 (d, J = 7.2 Hz, 1H), 7.46-7.36 (m, 3H), 4.04 (m, 2H), 3.88 (s, 3H),3.77 (s, 2H), 3.24 (m, 2H), 3.05 (m, 1H), 2.75 (m, 2H), 2.58 (s, 3H),2.22 (d, J = 14.0 Hz, 2H), 1.80 (d, J = 12.0 Hz, 2H). Example 158 LCMS:[M + H]⁺ 451.2; ¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J = 8.0 Hz, 1H), 7.66(d, J = 7.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 6.82 (dd, J = 8.0, 2.0Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 4.58-4.56(m, 1H), 4.25 (t, J = 4.4 Hz, 2H), 3.87 (s, 1H), 3.81-3.75 (m, 2H),3.28-3.22 (m, 4H), 3.04 (q, J = 7.2 Hz, 1H), 2.89 (s, 3H), 2.72-2.67 (m,2H), 2.57 (s, 3H), 2.24-2.20 (m, 2H), 1.78-1.75 (m, 2H).

Further example compounds of the invention prepared by the methodsdescribed herein are provided in Table 9.

TABLE 9 Example Name and structure LCMS: [M + H]⁺ Example 178

360.2 Example 179

359.2 Example 180

388.2 Example 181

332.2 Example 182

290.1 Example 183

318.1 Example 184

378.2 Example 185

392.2 Example 186

361.2 Example 187

376.2 Example 188

361.2 Example 189

361.2 Example 190

373.2 Example 191

304.1 Example 192

373.2 Example 193

453.2 Example 194

360.2 Example 195

425.1 Example 196

452.2 Example 197

361.1 Example 198

305.1 Example 199

442.1 Example 200

345.2 Example 201

454.1

Int-A39: 2-(Chloromethyl)-7-isobutylquinazolin-4(3H)-one

Step 1: 2-Amino-4-(2-methylprop-1-en-1-yl)benzoic acid

To a solution of 2-amino-4-bromo-benzoic acid (500 mg, 2.31 mmol, 1.0eq) in 1,4-dioxane/water (4:1, 20 mL) under a N₂ atmosphere was added4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (548 mg,3.01 mmol, 1.3 eq), Pd(dppf)Cl₂ (169 mg, 0.23 mmol, 0.1 eq) andpotassium carbonate (640 mg, 4.63 mmol, 2.0 eq) and the mixture washeated at 100° C. for 6 h. After cooling to RT, the mixture was dilutedwith water (20 mL) and extracted with EtOAc (40 mL×3). The combinedorganic layers were washed with water (40 mL), dried over Na₂SO₄ andconcentrated under reduced pressure to afford the title compound (400mg, 90%) as a brown oil. LCMS: [M+H]⁺ 192.2.

Step 2: Methyl 2-amino-4-(2-methylprop-1-en-1-yl)benzoate

Prepared from 2-amino-4-(2-methylprop-1-en-1-yl) benzoic acid accordingto the method described for Int-A20, step 3. LCMS: [M+H]⁺ 206.2.

Step 3: Methyl 2-amino-4-isobutylbenzoate

A solution of methyl 2-amino-4-(2-methylprop-1-enyl) benzoate (200 mg,0.97 mmol) and Pt/C (10% wet, 20 mg) in EtOAc (20 mL) was stirred at RTunder a H₂ atmosphere overnight. The mixture was filtered and thefiltrate was concentrated under reduced pressure to afford the titlecompound (200 mg, 99%) as a colorless oil. LCMS: [M+H]⁺ 208.2.

Step 4: 2-(Chloromethyl)-7-isobutylquinazolin-4(3H)-one

Prepared from methyl 2-amino-4-isobutylbenzoate and chloroacetonitrileaccording to the method described for Int-A16. LCMS: [M+H]⁺ 251.1.

Int-A40: 5-Bromo-2-(chloromethyl)-7-fluoroquinazolin-4(3H)-one

Prepared from 3-bromo-5-fluoroaniline according to the method describedfor Int-A20. LCMS: [M+H]⁺ 290.9;

¹HNMR (400 MHz, DMSO-d₆) δ 7.76 (dd, J=8.8, 2.8 Hz, 1H), 7.51 (dd,J=9.2, 2.4 Hz, 1H), 4.52 (s, 2H).

Int-A41:5-Chloro-2-(chloromethyl)-7-(cyclopentylamino)quinazolin-4(3H)-one

Step 1: Methyl 4-bromo-2-chloro-6-fluorobenzoate

Prepared from 4-bromo-2-chloro-6-fluorobenzoic acid according to themethod described for Int-A20, step 3.

¹HNMR (400 MHz, CDCl₃) δ 7.41 (s, 1H), 7.26-7.24 (m, 1H), 3.96 (s, 3H).

Step 2: Methyl 2-chloro-4-(cyclopentylamino)-6-fluorobenzoate

To a solution of methyl 4-bromo-2-chloro-6-fluorobenzoate (2.0 g, 7.48mmol, 1.0 eq) and cyclopentane amine (0.76 g, 8.97 mmol, 1.2 eq) intoluene (5 mL) under a N₂ atmosphere were added Cs₂CO₃ (4.87 g, 15.0mmol, 2.0 eq), BINAP (931 mg, 1.5 mmol, 0.2 eq) and Pd(OAc)₂ (168 mg,0.75 mmol, 0.1 eq) and the mixture was heated at reflux for 30 min.After cooling to RT, the mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography (petroleum ether:EtOAc, 10:1, v/v) to afford the titlecompound (2.0 g, 98%) as a colorless oil. LCMS: [M+H]⁺ 272.1.

Step 3: Methyl2-chloro-4-(cyclopentylamino)-6-((2,4-dimethoxybenzyl)amino)benzoate

To a solution of methyl 2-chloro-4-(cyclopentylamino)-6-fluorobenzoate(2.0 g, 7.36 mmol, 1.0 eq) and (2,4-dimethoxyphenyl)methanamine (3.69 g,22.1 mmol, 3.0 eq) in NMP (30 mL) under a N₂ atmosphere was added K₂CO₃(2.03 g, 14.7 mmol, 2.0 eq) and the mixture was heated at 100° C.overnight. After cooling to RT, the mixture was diluted with water (90mL) and extracted with EtOAc (30 mL×3). The combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (petroleum ether:EtOAc, 8:1 to5:1, v/v) to afford the title compound (1.6 g, 56%) as a white solid.LCMS: [M+H]⁺ 419.1.

Step 4: Methyl 2-amino-6-chloro-4-(cyclopentylamino)benzoate

To a solution of methyl2-chloro-4-(cyclopentylamino)-6-((2,4-dimethoxybenzyl)amino)benzoate(1.6 g, 3.82 mmol, 1.0 eq) in DCM (10 mL) was added TFA (5 mL) and themixture was stirred at RT for 30 min. The mixture was concentrated underreduced pressure and the residue was diluted with a saturated aqueousNa₂CO₃ solution (30 mL) and extracted with EtOAc (30 mL×3). The combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (petroleumether:EtOAc, 5:1, v/v) to afford the title compound (610 mg, 59%) as ayellow solid. LCMS: [M+H]⁺ 269.1.

Step 5:5-Chloro-2-(chloromethyl)-7-(cyclopentylamino)quinazolin-4(3H)-one

Prepared from methyl 2-amino-6-chloro-4-(cyclopentylamino)benzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 312.1.

Int-A42:2-(Chloromethyl)-7-(cyclopentylamino)-5-methoxyquinazolin-4(3H)-one

Step 1: Methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate

Prepared from methyl 4-bromo-2,6-difluorobenzoate according to themethod described for Int-A41, step 3. LCMS: [M+H]⁺ 398.0.

Step 2: 4-Bromo-2-((2,4-dimethoxybenzyl)amino)-6-methoxybenzoic Acid

To a solution of methyl4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate (3.98 g, 9.99mmol, 1.0 eq) in methanol (20 mL) and NMP (20 mL) was added NaH (60% w/wsuspension in oil, 2.0 g, 50.0 mmol, 5.0 eq) and the mixture was heatedat 120° C. overnight. After cooling to RT, the mixture was adjusted topH 4 with 6 M HCl and the resulting precipitate was collected byfiltration to afford the title compound (1.4 g, 35%) as a white solid.LCMS: [M+H]⁺ 396.0.

Step 3: Methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-methoxybenzoate

Prepared from 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-methoxybenzoicAcid according to the method described for Int-A20 step 3. LCMS: [M+H]⁺410.1.

Step 4: Methyl4-(cyclopentylamino)-2-((2,4-dimethoxybenzyl)amino)-6-methoxybenzoate

To a solution of methyl4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-methoxybenzoate (820 mg, 2.0mmol, 1.0 eq) and cyclopentanamine (255 mg, 3.0 mmol, 1.5 eq) in toluene(15 mL) under a N₂ atmosphere was added Cs₂CO₃ (1.95 g, 6.0 mmol, 3.0eq), Xantphos (231 mg, 0.4 mmol, 0.2 eq) and Pd(OAc)₂ (45 mg, 0.20 mmol,0.1 eq) and the mixture was heated at reflux for 8 h. After cooling toRT, the mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography(petroleum ether:EtOAc, 7:1, v/v) to afford the title compound (680 mg,82%) as a white solid. LCMS: [M+H]⁺ 415.2.

Step 5: Methyl 2-amino-4-(cyclopentylamino)-6-methoxy-benzoate

Prepared from methyl4-(cyclopentylamino)-2-((2,4-dimethoxybenzyl)amino)-6-methoxybenzoateaccording to the method described for Int-A41, step 4. LCMS: [M+H]⁺265.2.

Step 6:2-(Chloromethyl)-7-(cyclopentylamino)-5-methoxyquinazolin-4(3H)-one

Prepared from methyl 2-amino-4-(cyclopentylamino)-6-methoxy-benzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 308.1.

Int-A43:2-(Chloromethyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one

Step 1: Methyl 2-amino-4-(cyclopentylamino)-6-fluorobenzoate

Prepared from methyl 4-bromo-2,6-difluorobenzoate according to themethod described for Int 39, step 2, 3 and 4. LCMS: [M+H]⁺ 253.1.

Step 2:2-(Chloromethyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one

Prepared from methyl 2-amino-4-(cyclopentylamino)-6-fluorobenzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 296.1.

Int-A44: 7-Chloro-2-(chloromethyl)pyrido[2,3-d]pyrimidin-4(3H)-one

A solution of 2-amino-6-chloro-pyridine-3-carboxamide (500 mg, 2.91mmol, 1.0 eq) in 2-chloro-1,1,1-trimethoxy-ethane (5 mL) was heated at120° C. under a N₂ atmosphere for 3 h. The mixture was then filtered andthe filter cake was washed with EtOAc/petroleum ether (1:3, 20 mL) thendried under reduced pressure to afford the title compound (450 mg, ˜50%purity, 33%) as a brown solid, which was used without furtherpurification. LCMS: [M+H]⁺ 230.0.

Int-A45: 7-Bromo-2-(chloromethyl)-6-methoxyquinazolin-4(3H)-one

Step 1: Ethyl 2-amino-4-bromo-5-methoxybenzoate

Prepared from 4-bromo-5-fluoro-2-nitrobenzoic acid according to theprocedure described in WO2014128655.

Step 2: 7-Bromo-2-(chloromethyl)-6-methoxyquinazolin-4(3H)-one

Prepared from ethyl 2-amino-4-bromo-5-methoxybenzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 303.0.

Int-A46: 7-Bromo-2-(chloromethyl)-5-fluoroquinazolin-4(3H)-one

Step 1: Methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate

Prepared from methyl 4-bromo-2,6-difluorobenzoate and(2,4-dimethoxyphenyl)methanamine according to the method described forInt-A41, step 3. LCMS: [M+H]⁺ 398.0.

Step 2: 7-Bromo-2-(chloromethyl)-5-fluoroquinazolin-4(3H)-one

A mixture of methyl4-bromo-2-[(2,4-dimethoxyphenyl)methylamino]-6-fluoro-benzoate (100 g,251 mmol, 1.0 eq), 2-chloroacetonitrile (47.7 mL, 753 mmol, 3.0 eq) anda 4 M HCl in dioxane solution (300 mL) was heated at 100° C. overnight.After cooling to RT, the mixture was filtered and the collected solidwas purified by column chromatography (DCM:MeOH, 50:1 to 10:1, v/v) toafford the title compound (84 g, >100%) as a light-yellow solid, whichwas used in subsequent steps without further purification LCMS: [M+H]⁺290.9.

Int-A47:2-(Chloromethyl)-7-(cyclopentylamino)-5,6-difluoroquinazolin-4(3H)-one

Step 1: Methyl 6-amino-2,3,4-trifluorobenzoate

Prepared from 3,4,5-trifluoroaniline according to the method describedfor Int-A20, step 1, 2 and 3. LCMS: [M+H]⁺ 206.0.

Step 2: Methyl 6-amino-4-(cyclopentylamino)-2,3-difluorobenzoate

A mixture of methyl 6-amino-2,3,4-trifluoro-benzoate (2.05 g, 9.99 mmol,1.0 eq), cyclopentanamine (1.18 mL, 12.0 mmol) and K₂CO₃ (1.38 g, 9.99mmol, 1.0 eq) in DMSO (20 mL) was heated at 55° C. for 16 h. Aftercooling to RT, the mixture was diluted with EtOAc (100 mL), washed withbrine (20 mL×3) and the organic layer was concentrated under reducedpressure. The residue was purified by C18 reverse phase column (Biotage,40% to 80% ACN in water) to afford the title compound (1.1 g, 41%) as apale green solid. LCMS: [M+H]⁺ 271.1.

Step 3:2-(Chloromethyl)-7-(cyclopentylamino)-5,6-difluoroquinazolin-4(3H)-one

Prepared from methyl 6-amino-4-(cyclopentylamino)-2,3-difluorobenzoateand chloroacetonitrile according to the method described for Int-A16.LCMS: [M+H]⁺ 314.1.

Int-A48: 7-Bromo-2-(chloromethyl)-6-fluoroquinazolin-4(3H)-one

Step 1: Methyl 4-bromo-5-fluoro-2-nitrobenzoate

Prepared from 4-bromo-5-fluoro-2-nitrobenzoic acid according to themethod described for Int-A20, step 3.

¹HNMR (400 MHz, CDCl₃) δ 8.20 (d, J=5.6 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H),3.94 (s, 3H).

Step 2: Methyl 2-amino-4-bromo-5-fluorobenzoate

To a solution of methyl 4-bromo-5-fluoro-2-nitrobenzoate (2.0 g, 7.19mmol, 1.0 eq) in ethanol (20 mL) and water (10 mL) was added NH₄Cl (1.15g, 21.6 mmol, 3.0 eq) and zinc (1.41 g, 21.6 mmol, 3.0 eq) and themixture was heated at 40° C. for 2 h. After cooling to RT, the mixturewas filtered and the filtrate was concentrated under reduce pressure.The residue was diluted with water (50 mL) and extracted with EtOAc (50mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (petroleum ether:EtOAc, 20:1, v/v) to afford the titlecompound (390 mg, 22%) as a white solid. LCMS: [M+H]⁺ 248.0.

Step 3: 7-Bromo-2-(chloromethyl)-6-fluoroquinazolin-4(3H)-one

Prepared from methyl 2-amino-4-bromo-5-fluorobenzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 291.0.

Int-A49:2-(Chloromethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one

Step 1: Methyl 2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-hydroxybenzoate

To a solution of methyl4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate (50 g, 126 mmol,1.0 eq; see Int-A42, step 1) in 1,4-dioxane (150 mL) and water (150 mL)was added NaOH (12.6 g, 314 mmol, 3.0 eq), Pd₂(dba)₃ (2.3 g, 2.51 mmol,0.01 eq) and t-BuXphos (1.06 g, 2.51 mmol, 0.01 eq) and the mixture washeated at 90° C. under a N₂ atmosphere for 3 h. After cooling to RT, themixture was filtered and the filtrate was adjusted to pH 5 with 0.5 MHCl and extracted with EtOAc (300 mL×3). The combined organic layerswere dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography (petroleum ether:EtOAc,5:1, v/v) to afford the title compound (25 g, 48%) as a yellow solid.LCMS: [M+H]⁺ 336.1.

Step 2: Methyl4-(cyclopropylmethoxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate

To a solution of methyl2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-hydroxybenzoate (3.2 g, 8.11mmol, 1.0 eq) in DMF (20 mL) was added bromomethylcyclopropane (1.31 g,9.73 mmol, 1.2 eq) and K₂CO₃ (2.24 g, 16.2 mmol, 2.0 eq) and the mixturewas heated at 80° C. for 3 h. After cooling to RT, the mixture wasdiluted with water (100 mL) and extracted with EtOAc (100 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography(petroleum ether:EtOAc, 10/1, v/v) to afford the title compound (2.4 g,76%) as a white solid. LCMS: [M+H]⁺ 390.2.

Step 3: Methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate

To a solution of methyl4-(cyclopropylmethoxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate(1.6 g, 4.11 mmol, 1.0 eq) in DCM (8.0 mL) was added TFA (4.0 mL) andthe mixture was stirred at RT for 2 h. The mixture was concentratedunder reduced pressure and the residue was purified by columnchromatography (DCM:MeOH, 20/1, v/v) to afford the title compound (0.9g, 91%) as a brown solid. LCMS: [M+H]⁺ 240.1.

Step 4:2-(Chloromethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one

Prepared from methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 283.1.

Alternative Synthesis of Int-A49:2-(Chloromethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one

Step 1: Methyl 4-(cyclopropylmethoxy)-2,6-difluorobenzoate

A mixture of methyl 2,6-difluoro-4-hydroxybenzoate, preparation of whichis described in Example 333, Step 4 (180 g, 957 mmol),(bromomethyl)cyclopropane (102 mL, 1.05 mol) and K₂CO₃ (330 g, 2.39 mol)in DMSO (1 L) was heated at 80° C. overnight. The mixture was dilutedwith water (5 L) and extracted with EtOAc (1 L×3). The combined organicextracts were washed with water (800 mL), brine (800 mL), dried overNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound (214 g, 92%) as a brown oil. LCMS: [M+H]⁺243.1.

Step 2: Methyl4-(cyclopropylmethoxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate

A mixture of methyl 4-(cyclopropylmethoxy)-2,6-difluorobenzoate (214 g,881 mmol), (2,4-dimethoxyphenyl)methanamine (139 mL, 926 mmol) and K₂CO₃(243 g, 1.76 mol) in NMP (1 L) was heated at 80° C. overnight. Themixture was poured into water (5 L) and the resulting precipitate wascollected by filtration and washed with water (800 mL). The filter cakewas dissolved in DCM (2.5 L) and washed with brine (800 mL). The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure togive the title compound (343 g, 99%) as an off-white solid. LCMS:[M+Na]⁺ 412.1.

Step 3: Methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate

To a solution of methyl4-(cyclopropylmethoxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate(1.6 g, 4.11 mmol, 1.0 eq) in DCM (8.0 mL) was added TFA (4.0 mL) andthe mixture was stirred at RT for 2 h. The mixture was concentratedunder reduced pressure and the residue was purified by columnchromatography (DCM:MeOH, 20/1, v/v) to afford the title compound (0.9g, 91%) as a brown solid. LCMS: [M+H]⁺ 240.1.

Step 4:2-(Chloromethyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-one

Prepared from methyl 2-amino-4-(cyclopropylmethoxy)-6-fluorobenzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 283.1.

Int-A50:2-(Chloromethyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one

Step 1: Methyl 2-amino-6-fluoro-4-((tetrahydro-2H-pyran-4-yl)methoxy)Benzoate

Prepared from methyl2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-hydroxybenzoate and4-(bromomethyl)tetrahydro-2H-pyran according to the method described forInt-A49, step 2 and 3. LCMS: [M+H]⁺ 284.1.

Step 2: 2-(Chloromethyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl) methoxy)quinazolin-4(3H)-one

Prepared from methyl2-amino-6-fluoro-4-((tetrahydro-2H-pyran-4-yl)methoxy) benzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 327.1.

Int-A51:2-(Chloromethyl)-7-(cyclobutylmethoxy)-5-methylquinazolin-4(3H)-one

Step 1: Methyl 4-bromo-2-fluoro-6-methylbenzoate

Prepared from 4-bromo-2-fluoro-6-methylbenzoic acid according to themethod described for Int-A20 step 3.

Step 2: Methyl 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-methylbenzoate

Prepared from methyl 4-bromo-2-fluoro-6-methylbenzoate and(2,4-dimethoxyphenyl)methanamine according to the method described forInt-A41, step 3. LCMS: [M+H]⁺ 394.1.

Step 3: Methyl 2-amino-4-(cyclobutylmethoxy)-6-methylbenzoate

Prepared from methyl4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-methylbenzoate and(bromomethyl)cyclobutane according to the method described for Int-A49,step 1, 2 and 3. LCMS: [M+H]⁺ 250.1.

Step 4:2-(Chloromethyl)-7-(cyclobutylmethoxy)-5-methylquinazolin-4(3H)-one

Prepared from methyl 2-amino-4-(cyclobutylmethoxy)-6-methylbenzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 293.1.

Int-A52:2-(Chloromethyl)-5-fluoro-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one

Step 1: (Tetrahydrofuran-3-yl)methyl methanesulfonate

Prepared from (tetrahydrofuran-3-yl)methanol according to the methoddescribed for Int-B3, step 1 and used directly in the next step.

Step 2: Methyl 2-amino-6-fluoro-4-((tetrahydrofuran-3-yl)methoxy)Benzoate

Prepared from methyl2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-hydroxybenzoate and(tetrahydrofuran-3-yl)methyl methanesulfonate according to the methoddescribed for Int-A47, step 2 and 3. LCMS: [M+H]⁺ 270.1.

Step 3. 2-(Chloromethyl)-5-fluoro-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one

Prepared from methyl 2-amino-6-fluoro-4-((tetrahydrofuran-3-yl)methoxy)benzoate and chloroacetonitrile according to the method described forInt-A16. LCMS: [M+H]⁺ 313.0.

Int-A53: 2-(Chloromethyl)-5-fluoro-7-hydroxyquinazolin-4(3H)-one

Step 1: Methyl 2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-hydroxybenzoate

To a solution of methyl4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate (50.0 g, 125mmol) in 1,4-dioxane (150 mL) and water (150 mL) was added KOH (14.1 g,251.1 mmol), Pd₂(dba)₃ (1.15 g, 1.26 mmol) and t-BuXphos (1.06 g, 2.51mmol) and the mixture was heated at 90° C. under a N₂ atmosphere for 3h. After cooling to RT, the mixture was extracted with EtOAc (300 mL).The organic layer was washed with brine (100 mL×3), dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified bycolumn chromatography (Petroleum ether:EtOAc, 5:1, v/v) to afford thetitle compound (29.0 g, 55%) as a yellow solid. LCMS: [M+H]⁺ 336.0.

Step 2. 2-(Chloromethyl)-5-fluoro-7-hydroxyquinazolin-4(3H)-one

Prepared from methyl2-((2,4-dimethoxybenzyl)amino)-6-fluoro-4-hydroxybenzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 229.0.

Int-B14: Ethyl 4-(acetylthio) cyclohexane-1-carboxylate

Prepared from ethyl 4-hydroxycyclohexane-1-carboxylate according to themethod described for Int-B3, step 1 and 2 and obtained as a 2:1 mixtureof cis and trans isomers.

¹H NMR (400 MHz, CDCl₃) 4.10-4.02 (m, 2H), 3.70 (m, 0.67H), 3.31 (m,0.33H), 2.51-2.44 (m, 1H), 2.24 (s, 2H), 2.23 (s, 1H), 2.19-2.17 (m,2H), 2.04-1.91 (m, 4H), 1.66-1.46 (m, 2H), 1.20-1.17 (m, 3H).

Int-B15: Ethyl 2-(trans-4-(acetylthio)cyclohexyl)acetate

Step 1: Ethyl 2-(cis-4-hydroxycyclohexyl)acetate

Prepared from ethyl 2-(4-hydroxyphenyl)acetate according to theprocedure described in WO2006/044524.

Step 2: Ethyl 2-(trans-4-(acetylthio)cyclohexyl)acetate

Prepared from ethyl 2-(cis-4-hydroxycyclohexyl)acetate according to themethod described for Int-B3, step 1 and 2.

¹H NMR (400 MHz, CDCl₃) δ 4.06 (q, J=7.2 Hz, 2H), 3.26 (m, 1H), 2.29 (s,3H), 2.18 (d, J=6.8 Hz, 2H), 1.99-1.96 (m, 2H), 1.83-1.79 (m, 3H),1.43-1.33 (m, 2H), 1.18 (t, J=7.2 Hz, 3H), 1.13-1.03 (m, 2H)

Int-B16: S-((cis)-4-Hydroxy-4-methylcyclohexyl) Ethanethioate

Step 1: (trans)-4-Hydroxy-4-methylcyclohexyl Methanesulfonate

Prepared from (cis)-1-methylcyclohexane-1,4-diol according to the methoddescribed for Int-B3, step 1 ¹H NMR (400 MHz, DMSO-d₆) δ 4.60-4.49 (m,1H), 3.15 (s, 3H), 1.86-1.70 (m, 4H), 1.63-1.51 (m, 2H), 1.45-1.32 (m,2H), 1.09 (s, 3H). One signal (OH) not observed.

Step 2: S-((cis)-4-Hydroxy-4-methylcyclohexyl) Ethanethioate

Prepared from (trans)-4-hydroxy-4-methylcyclohexyl Methanesulfonateaccording to the method described for Int-B3, step 2. ¹H NMR (400 MHz,DMSO-d₆) δ 3.60-3.50 (m, 1H), 2.29 (s, 3H), 2.02-1.89 (m, 2H), 1.49-1.37(m, 6H), 1.08 (s, 3H). One signal (OH) not observed.

Int-C12:S-((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl) ethanethioate

Prepared from Int-A41 and KSAc according to the method described forInt-C1. LCMS: [M+H]⁺336.1.

Example 202:7-Isobutyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of Int-A39 (100 mg, 0.40 mmol, 1.0 eq) and Int-B1 (64 mg,0.40 mmol, 1.0 eq) in THF (2 mL) was added 2 M NaOH (0.8 mL) and themixture was stirred under a N₂ atmosphere at RT overnight. The mixturewas diluted with water (5 mL) and extracted with EtOAc (20 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by prep-TLC (DCM:MeOH, 20:1,v/v) to afford the title compound (45 mg, 34%) as a yellow solid. LCMS:[M+H]⁺ 333.2;

¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.39(s, 1H), 7.31 (d, J=8.0 Hz, 1H), 3.81 (m, 2H), 3.66 (s, 2H), 3.34-3.28(m, 2H), 3.06 (m, 1H), 2.60 (d, J=7.2 Hz, 2H), 1.91 (m, 3H), 1.45 (m,2H), 0.88 (d, J=6.4 Hz, 6H).

Example 203:7-(Cyclopentylamino)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1:5-Bromo-7-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from Int-A40 and Int-B1 according to the method described forExample 202. LCMS: [M+H]⁺ 373.0.

Step 2:7-Fluoro-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of 5-bromo-7-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl) quinazolin-4(3H)-one (373 mg, 1.0 mmol, 1.0 eq) and2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (376 mg, 3.0 mmol, 3.0 eq)in dioxane/water (10:1, 22 mL) under a N₂ atmosphere was added K₂CO₃(276 mg, 2.0 mmol, 2.0 eq) and PdCl₂(dppf) (82 mg, 0.1 mmol, 0.1 eq) andthe mixture was heated at 100° C. overnight. After cooling to RT, themixture was filtered and the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography (DCM:MeOH,100:1, v/v) to afford the title compound (230 mg, 75%) as a pink solid.LCMS: [M+H]⁺ 309.1.

Step 3:7-(Cyclopentylamino)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from 7-fluoro-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl) quinazolin-4(3H)-one and cyclopentanamine according to themethod described for Example 126. LCMS: [M+H]⁺374.2;

¹H NMR (400 MHz, CD₃OD) δ 6.54 (s, 1H), 6.49 (s, 1H), 3.95-3.80 (m, 3H),3.63 (s, 2H), 3.42 (t, J=10.4 Hz, 2H), 3.06-2.95 (m, 1H), 2.69 (s, 3H),2.09-1.98 (m, 2H), 1.95-1.89 (m, 2H), 1.81-1.75 (m, 2H), 1.72-1.63 (m,2H), 1.63-1.50 (m, 4H).

Example 204:cis-4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide

Step 1:4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid

Prepared from Int-A1 and Int-B14 according to the method described forExample 202. This coupling reaction proceeded with concomitanthydrolysis of the ester to give the title compound directly. LCMS:[M+H]⁺ 333.1.

Step 2:cis-4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid andtrans-4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid

4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid was further purified by prep-HPLC (Agilent 10 prep-C18, 10 μm,250×21.2 mm column, eluting with a gradient of MeOH in water with 0.1%TFA, at a flow rate of 20 mL/min) to afford the trans isomer as thefirst eluting isomer, LCMS: [M+H]⁺ 333.1 and the cis isomer as thesecond eluting isomer, LCMS: [M+H]⁺ 333.1

Step 3:cis-4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide

Prepared fromcis-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid and NH₄Cl according to the method described for Example 77, step 2.LCMS: [M+H]⁺ 332.2;

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.2 Hz,1H), 7.39 (t, J=8.0 Hz, 1H), 3.72 (s, 2H), 3.26-3.22 (m, 1H), 2.58 (s,3H), 2.31-2.23 (m, 1H), 1.95-1.76 (m, 6H), 1.66-1.56 (m, 2H).

Example 205:trans-4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide

Prepared fromtrans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid and NH₄Cl according to the method described for Example 77, step 2.LCMS: [M+H]⁺ 332.2;

¹H NMR (400 MHz, CD₃OD) δ 8.03 (d, J=7.6 Hz, 1H), 7.66 (d, J=6.8 Hz,1H), 7.38 (t, J=7.6 Hz, 1H), 3.75 (s, 2H), 2.74-2.81 (m, 1H), 2.60 (s,3H), 2.25-2.14 (m, 3H), 1.90-1.87 (m, 2H), 1.53-1.43 (m, 2H), 1.38-1.29(m, 2H).

Example 206:5-Chloro-7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Step 1: tert-Butyl4-(((5-chloro-7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

Prepared from Int-A41 and Int-B2 according to the method described forExample 202. LCMS: [M+H]⁺ 493.2.

Step 2:5-Chloro-7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Prepared from tert-butyl4-(((5-chloro-7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylateaccording to the method described for Example 48, step 2. LCMS: [M+H]⁺393.2;

¹H NMR (400 MHz, CD₃OD) δ 6.91 (d, J=2.0 Hz, 1H), 6.73 (d, J=2.0 Hz,1H), 4.00-3.96 (m, 2H), 3.90-3.84 (m, 1H), 3.46-3.37 (m, 2H), 3.35-3.26(m, 1H), 3.16-3.10 (m, 2H), 2.37-2.28 (m, 2H), 2.12-2.04 (m, 2H),1.84-1.64 (m, 6H), 1.62-1.53 (m, 2H).

Example 207:7-(Cyclopentylamino)-5-methoxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from Int-A42 and Int-B1 according to the method described forExample 202. LCMS: [M+H]⁺ 390.1.

¹H NMR (400 MHz, DMSO-d₆) δ 11.3 (s, 1H), 6.52 (d, J=6.0 Hz, 1H), 6.19(s, 1H), 6.12 (s, 1H), 3.87-3.76 (m, 3H), 3.73 (s, 3H), 3.51 (s, 2H),3.33-3.27 (m, 2H), 3.10-2.97 (m, 1H), 2.01-1.82 (m, 4H), 1.76-1.63 (m,2H), 1.60-1.52 (m, 2H), 1.52-1.36 (m, 4H).

Example 208: Methyl4-(((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

Step 1: tert-Butyl4-(((7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

Prepared from Int-A9 and Int-B2 according to the method described forExample 202. LCMS: [M+H]⁺ 394.1.

Step 2: tert-Butyl4-(((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

Prepared from tert-butyl4-(((7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylateand cyclopentanamine according to the method described for Example 126.LCMS: [M+H]⁺ 459.2.

Step 3:7-(Cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Prepared from tert-butyl4-(((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylateaccording to the method described for Example 48, step 2. LCMS: [M+H]⁺359.2.

Step 4: Methyl4-(((7-(cyclopentylamino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

To a solution of7-(cyclopentylamino)-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride (110 mg, 0.28 mmol, 1.0 eq) in NMP (4 mL) was added K₂CO₃(85 mg, 0.61 mmol, 2.2 eq) followed by methyl carbonochloridate (32 mg,0.33 mmol, 1.2 eq) dropwise and the mixture was heated at 40° C.overnight. After cooling to RT, the mixture was diluted with water (30mL) and extracted with EtOAc (30 mL×3). The combined organic layers werewashed with water (20 mL), dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by prep-TLC (DCM:MeOH, 20:1,v/v) to afford the title compound (5 mg, 4%) as a yellow solid. LCMS:[M+H]⁺ 417.2;

¹H NMR (400 MHz, CD₃OD) δ 7.85 (d, J=8.8 Hz, 1H), 6.80 (dd, J=8.8, 2.4Hz, 1H), 6.62 (s, 1H), 4.00-3.90 (m, 2H), 3.91-3.82 (m, 1H), 3.68 (s,2H), 3.66 (s, 3H), 3.05-2.94 (m, 3H), 2.11-1.93 (m, 4H), 1.84-1.73 (m,2H), 1.73-1.64 (m, 2H), 1.64-1.54 (m, 2H), 1.52-1.39 (m, 2H).

Example 209:2-((trans)-4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide

Step 1:2-(trans-4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)aceticacid

Prepared from Int-A1 and Int-B15 according to the method described forExample 202. This coupling reaction proceeded with concomitanthydrolysis of the ester to give the title compound directly. LCMS:[M+H]⁺ 347.1.

Step 2:2-((trans)-4-(((8-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide

Prepared from2-(trans-4-(((8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)aceticacid and NH₄Cl according to the method described for Example 77, step 2.LCMS: [M+H]⁺ 346.2;

¹H NMR (400 MHz, DMSO-d₆) δ 12.3 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.66(d, J=6.8 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.20 (br s, 1H), 6.89 (br s,1H), 3.65 (s, 2H), 2.72-2.80 (m, 1H), 2.50 (3H, obscured by solventpeak), 2.00-2.09 (m, 2H), 1.89 (d, J=7.6 Hz, 2H), 1.70-1.73 (m, 2H),1.65-1.59 (m, 1H), 1.26-1.18 (m, 2H), 0.98-0.88 (m, 2H).

Example 210:7-(Cyclopentylamino)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-oneHydrochloride

Step 1: tert-butyl cis-3-fluoro-4-hydroxypiperidine-1-carboxylate

Prepared from tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylateaccording to literature WO2011036576.

Step 2: tert-Butylcis-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate

Prepared from tert-butyl cis-3-fluoro-4-hydroxypiperidine-1-carboxylateaccording to the method described for Int B3, step 1. LCMS: [M+H]⁺298.1.

Step 3: tert-Butyltrans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoropiperidine-1-carboxylate

To a solution of Int-C12 (100 mg, 0.30 mmol, 1.0 eq) and tert-butylcis-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (177 mg,0.90 mmol, 3.0 eq) in DMF (2 mL) at RT under a N₂ atmosphere was added 2M NaOH (0.6 mL) and the mixture was heated at 100° C. for 3 h. Themixture was poured into water (5 mL), extracted with EtOAc (10 mL×3) andthe combined organic layers were washed with water (10 mL), dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby prep-TLC (petroleum ether:EtOAc, 1:2, v/v) to afford the titlecompound (30 mg, 20%) as a yellow solid. LCMS: [M+H]⁺ 495.2.

Step 4:7-(Cyclopentylamino)-5-fluoro-2-(((trans-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-oneHydrochloride

Prepared from tert-butyltrans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoropiperidine-1-carboxylateaccording to the method described for Example 48, step 2. LCMS: [M+H]⁺395.1;

¹HNMR (400 MHz, DMSO-d₆) δ 12.0 (br s, 1H), 9.37 (br s, 1H), 9.09 (br s,1H), 6.50-6.46 (m, 2H), 4.96-4.84 (m, 1H), 3.83-3.74 (m, 3H), 3.53-3.34(m, 2H), 3.28-3.18 (m, 1H), 3.12-2.97 (m, 2H), 2.34-2.22 (m, 1H),1.99-1.93 (m, 2H), 1.85-1.77 (m, 1H), 1.42-1.73 (m, 6H).

Example 211:7-(Cyclopentylamino)-5-fluoro-2-((((3S,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-oneand7-(Cyclopentylamino)-5-fluoro-2-((((3R,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

Example 210 was further purified by chiral prep-HPLC (Chiralpak IE-3, 3μm, 0.46×5 cm column, eluting with a gradient of MTBE (0.1% DEA):IPA50:50 at a flow rate of 1.0 mL/min), to afford the title compounds withretention times of 1.99 minutes (211a) and 2.72 minutes (211b).

Example 211a

LCMS: [M+H]⁺ 395.2;

¹H NMR (400 MHz, CD₃OD) δ 6.48-6.43 (m, 2H), 4.84-4.80 (m, 1H),3.86-3.70 (m, 3H), 3.45-3.30 (m, 2H), 3.15-2.96 (m, 3H), 2.40-2.28 (m,1H), 2.07-2.02 (m, 2H), 1.80-1.52 (m, 7H).

Example 211b

LCMS: [M+H]⁺ 395.2;

¹H NMR (400 MHz, CD₃OD) δ 6.48-6.42 (m, 2H), 4.84-4.80 (m, 1H),3.86-3.72 (m, 3H), 3.31-3.20 (m, 2H), 2.96-2.74 (m, 3H), 2.20-2.17 (m,1H), 2.07-2.00 (m, 2H), 1.80-1.52 (m, 7H).

Example 212:7-(Cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-oneHydrochloride

Step 1: tert-Butyl trans-3-fluoro-4-hydroxypiperidine-1-carboxylate

Prepared from tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylateaccording to literature WO2011036576.

Step 2: tert-Butyltrans-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate

Prepared from tert-butyltrans-3-fluoro-4-hydroxypiperidine-1-carboxylate according to the methoddescribed for Int B3, step 1. LCMS: [M+H]⁺ 298.1.

Step 3: tert-Butylcis-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoropiperidine-1-carboxylate

Prepared from Int-C12 and tert-butyltrans-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate accordingto the method described for Example 210, step 3. LCMS: [M+H]⁺ 495.2.

Step 4:7-(Cyclopentylamino)-5-fluoro-2-(((cis-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-oneHydrochloride

Prepared from tert-butylcis-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoropiperidine-1-carboxylateaccording to the method described for Example 48, step 2. LCMS: [M+H]⁺395.2;

¹H NMR (400 MHz, DMSO-d₆) δ 11.9 (br s, 1H), 9.28 (br s, 1H), 8.67 (brs, 1H), 7.00 (br s, 1H), 6.48-6.42 (m, 2H), 5.09 (d, J=44.8 Hz, 1H),3.84-3.65 (m, 3H), 3.57 (m, 1H), 3.43-3.16 (m, 3H), 2.96 (m, 1H),2.09-1.82 (m, 4H), 1.72-1.64 (m, 2H), 1.63-1.52 (m, 2H), 1.52-1.41 (m,2H).

Example 213:7-(Cyclopentylamino)-5-fluoro-2-((((3R,4S)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-oneand7-(cyclopentylamino)-5-fluoro-2-((((3S,4R)-3-fluoropiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

Example 212 was further purified by chiral prep-HPLC (Chiralpak IG-3, 3μm, 0.46×10 cm column, eluting with a gradient of MTBE (0.1% DEA):EtOH70:30 at a flow rate of 1.0 mL/min) to afford the title compounds withretention times of 3.79 minutes (213a) and 4.87 minutes (213b).

Example 213a

LCMS: [M+H]⁺ 395.2;

¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (br s, 1H), 6.84-6.83 (m, 1H),6.43-6.36 (m, 2H), 4.69-4.57 (m, 1H), 3.81-3.77 (m, 1H), 3.60-3.51 (m,2H), 3.37-3.02 (m, 2H), 2.87-2.83 (m, 1H), 2.70-2.51 (m, 2H), 2.50-2.43(m, 1H), 1.97-1.94 (m, 2H), 1.65-1.48 (m, 8H).

Example 213b

LCMS: [M+H]⁺ 395.2;

¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (br s, 1H), 6.84-6.83 (m, 1H),6.43-6.36 (m, 2H), 4.69-4.57 (m, 1H), 3.81-3.77 (m, 1H), 3.60-3.51 (m,2H), 3.37-3.02 (m, 2H), 2.87-2.83 (m, 1H), 2.70-2.51 (m, 2H), 2.50-2.43(m, 1H), 1.97-1.94 (m, 2H), 1.65-1.48 (m, 8H).

Example 214:7-(Cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1: tert-Butyl4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

Prepared from Int-A43 and Int-B2 according to the method described forExample 202. LCMS: [M+H]⁺ 477.1.

Step 2:7-(Cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Prepared from tert-butyl4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylateaccording to the method described for Example 48, step 2. LCMS: [M+H]⁺377.1.

Step 3:7-(Cyclopentylamino)-5-fluoro-2-(((1-(2-hydroxyacetyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution7-(cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride (100 mg, 0.24 mmol, 1.0 eq) and Et₃N (75 mg, 0.72 mmol,3.0 eq) in DMF (3 mL) were added 2-hydroxyacetic acid (37 mg, 0.48 mmol,2.0 eq), EDCI (98 mg, 0.51 mmol, 2.1 eq) and HOBt (68 mg, 0.51 mmol, 2.1eq) and the mixture was stirred at RT overnight. The mixture was dilutedwith water (10 mL) and extracted with EtOAc (10 mL×3). The combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by prep-TLC (DCM:MeOH, 10:1, v/v) toafford the title compound (35 mg, 33%) as a white solid. LCMS: [M+H]⁺435.2;

¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 6.82 (d, J=6.4 Hz, 1H), 6.41(d, J=14.0 Hz, 1H), 6.36 (s, 1H), 4.47 (t, J=5.6 Hz, 1H), 4.11-4.03 (m,3H), 3.78 (m, 1H), 3.62-3.58 (m, 1H), 3.56 (s, 2H), 3.05-3.03 (m, 2H),2.90-2.80 (m, 1H), 2.02-1.86 (m, 4H), 1.67-1.65 (m, 2H), 1.57-1.56 (m,2H) 1.50-1.29 (m, 4H).

Example 215:2-((Cyclohexylthio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-one

Prepared from Int-A43 and cyclohexanethiol according to the methoddescribed for Example 202. LCMS: [M+H]⁺ 376.1;

¹H NMR (400 MHz, DMSO-d₆) δ 11.6 (s, 1H), 6.81 (d, J=6.8 Hz, 1H), 6.41(dd, J=13.6, 2.4 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H), 3.83-3.75 (m, 1H),3.51 (s, 2H), 2.87-2.74 (m, 1H), 2.02-1.87 (m, 4H), 1.75-1.60 (m, 4H),1.60-1.39 (m, 5H), 1.30-1.15 (m, 5H).

Example 216:cis-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid and Example 217:trans-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid

Step 1:4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid

Prepared from Int-A43 and Int-B14 according to the method described forExample 202. This coupling reaction proceeded with concomitanthydrolysis of the ester to give the title compound directly. LCMS:[M+H]⁺ 420.1.

Step 2:cis-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid andtrans-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid

4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid was further purified by prep-HPLC (Agilent 10 prep-C18, 10 μm,250×21.2 mm column, eluting with a gradient of MeOH in water with 0.1%TFA, at a flow rate of 20 mL/min) to afford the title compounds.

Example 216

LCMS: [M+H]⁺ 420.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.0 (br s, 1H), 6.90 (br s, 1H), 6.43 (d,J=13.6 Hz, 1H), 6.37 (s, 1H), 3.82-3.76 (m, 1H), 3.52 (s, 2H), 3.09 (m,1H), 2.36-2.33 (m, 1H), 1.99-1.91 (m, 2H), 1.79-1.76 (m, 4H), 1.67-1.66(m, 2H), 1.59-1.49 (m, 6H), 1.48-1.43 (m, 2H).

Example 217

LCMS: [M+H]⁺ 420.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.0 (br s, 1H), 7.07 (br s, 1H), 6.45 (dd,J=13.6, 2.0 Hz, 1H), 6.39 (d, J=1.6 Hz, 1H), 3.96 (s, 1H), 3.82-3.76 (m,1H), 3.59 (s, 2H), 2.79-2.73 (m, 1H), 2.23-2.22 (m, 1H), 2.03-1.89 (m,6H), 1.70-1.66 (m, 2H), 1.59-1.50 (m, 2H), 1.48-1.42 (m, 2H), 1.38-1.20(m, 4H).

Example 218:trans-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxamide

Prepared fromtrans-4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexane-1-carboxylicacid and NH₄Cl according to the method described for Example 77, step 2.LCMS: [M+H]⁺ 419.1;

¹H NMR (400 MHz, DMSO-d₆) δ 11.6 (br s, 1H), 7.17 (s, 1H), 6.83 (d,J=6.4 Hz, 1H), 6.66 (s, 1H), 6.41 (d, J=14.0 Hz, 1H), 6.36 (s, 1H),3.81-3.76 (m, 1H), 3.53 (s, 2H), 3.17 (d, J=5.2 Hz, 1H), 2.75-2.68 (m,1H), 2.08-2.02 (m, 2H), 1.97-1.91 (m, 2H), 1.78-1.75 (m, 2H), 1.70-1.63(m, 2H), 1.61-1.64 (m, 2H), 1.49-1.43 (m, 2H), 1.39-1.29 (m, 2H),1.23-1.14 (m, 2H).

Example 219:7-(Cyclopropylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of7-bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one(200 mg, 0.41 mmol, 1.0 eq) in 1,4-dioxane (2 mL) and water (2 mL) undera N₂ atmosphere was added t-BuXPhos (70 mg, 0.16 mmol, 0.4 eq),Pd₂(dba)₃ (38 mg, 0.04 mmol, 0.1 eq) and sodium hydroxide (49 mg, 1.24mmol, 3.0 eq) and the mixture was heated at 90° C. overnight. Aftercooling to RT, t-Bu₄NBr (322 mg, 1 mmol, 2.5 eq) andbromomethylcyclopropane (696 mg, 5.16 mmol, 12.0 eq) were added and themixture was heated at 40° C. overnight. Loss of the SEM protecting grouphad also occurred in this reaction to give the title compound directly.After cooling to RT, the mixture was diluted with water (30 mL) andextracted with EtOAc (50 mL×3). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by prep-TLC (petroleum ether:EtOAc, 1:1, v/v) to afford thetitle compound (10 mg, 10%) as a white solid. LCMS: [M+H]⁺ 347.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.1 (br s, 1H), 7.97 (d, J=8.8 Hz, 1H),7.06 (dd, J=8.8, 2.4 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 3.95 (d, J=7.2 Hz,2H), 3.85-3.78 (m, 2H), 3.64 (s, 2H), 3.31-3.27 (m, 2H), 3.10-3.02 (m,1H), 1.92-1.85 (m, 2H), 1.50-1.40 (m, 2H), 1.33-1.21 (m, 1H), 0.65-0.55(m, 2H), 0.40-0.31 (m, 2H).

Example 220:4-(((7-(Cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-N,N-dimethylpiperidine-1-carboxamide

To a solution of7-(cyclopentylamino)-5-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride (100 mg, 0.24 mmol, 1.0 eq) and Et₃N (74 mg, 0.72 mmol,3.0 eq) in DCM (4.0 mL) under a N₂ atmosphere was addedN,N-dimethylcarbamoyl chloride (31 mg, 0.29 mmol, 1.2 eq) and themixture was stirred at 25° C. for 2 h. The mixture was diluted withwater (30 mL) and extracted with EtOAc (40 mL×2). The combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by prep-TLC (DCM:MeOH, 15:1, v/v) to afford thetitle compound (50 mg, 46%) as a white solid. LCMS: [M+H]⁺ 448.2;

¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 6.82 (d, J=6.4 Hz, 1H), 6.41(d, J=14.0 Hz, 1H), 6.36 (s, 1H), 3.82-3.75 (m, 1H), 3.55 (s, 2H),3.46-3.42 (m, 2H), 3.01-2.94 (m, 1H), 2.78-2.75 (m, 2H), 2.70 (s, 6H),1.98-1.90 (m, 4H), 1.72-1.63 (m, 2H), 1.61-1.52 (m, 2H), 1.50-1.35 (m,4H).

Example 221:2-(((Cis-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

Step 1: 6-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ol

Prepared from 3,4-dihydro-2H-pyran-2-carbaldehyde according toliterature Bioorg. Med. Chem. 2006, 14, 3953. The product was obtainedas a 7:3 mixture of trans/cis isomers.

Step 2:trans-6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ylMethanesulfonate andcis-6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ylMethanesulfonate

To a solution of6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ol (1.1 g,2.97 mmol, 1.0 eq) and Et₃N (450 mg, 4.45 mmol, 1.5 eq) in DCM (25 mL)under a N₂ atmosphere was added methanesulfonyl chloride (408 mg, 3.56mmol, 1.2 eq) and the mixture was stirred at RT for 2 h. The mixture wasdiluted with water (50 mL), extracted with DCM (20 mL×3) and thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography(petroleum ether:EtOAc, 1:0 to 10:1, v/v) to afford the trans isomer(730 mg, 55%) and cis isomer (330 mg, 25%) as white solids.

Trans isomer: ¹H NMR (400 MHz, CDCl₃) δ 7.66-7.36 (m, 10H), 4.64-4.58(m, 1H), 4.14-4.11 (m, 1H), 3.72-3.71 (m, 1H), 3.69-3.31 (m, 3H), 3.05(s, 3H), 2.33-2.30 (m, 1H), 1.90-1.87 (m, 1H), 1.73-1.70 (m, 1H),1.48-1.45 (m, 1H), 1.09 (s, 9H).

Cis isomer: ¹H NMR (400 MHz, CDCl₃) δ 7.61-7.31 (m, 10H), 4.10-4.07 (m,1H), 3.70-3.67 (m, 1H), 3.66-3.40 (m, 4H), 3.02 (s, 3H), 2.18-2.14 (m,1H), 1.80-1.56 (m, 3H), 0.99 (s, 9H).

Step 3: 2-(((cis-6-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

Prepared from Int-C1 andtrans-6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ylMethanesulfonate according to the method described for Example 210, step3. LCMS: [M+H]⁺559.2.

Step 4:2-(((cis-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one

To a solution of 2-(((cis6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-8-methylquinazolin-4(3H)-one(120 mg, 0.21 mmol, 1.0 eq) in DCM (2 mL) was added TBAF (0.64 mL, 0.64mmol, 3.0 eq) and the mixture was stirred at RT for 16 h. The mixturewas diluted with DCM (10 mL) and washed with water (5 mL) and brine (5mL), dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-TLC (DCM:MeOH, 20:1, v/v) followed by C18reverse phase column (Biotage, 0% to 40% MeCN in water) to afford thetitle compound (12 mg, 17%) as a white solid. LCMS: [M+H]⁺ 321.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.65(d, J=7.2 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 4.60 (t, J=5.6 Hz, 1H), 3.83(d, J=12.0 Hz, 1H), 3.68 (dd, J=12.0, 2.4 Hz, 1H), 3.63 (d, J=2.0 Hz,2H), 3.29-3.22 (m, 3H), 3.19 (m, 1H), 2.49 (3H, obscured by solventpeak), 1.93-1.85 (m, 2H), 1.52-1.38 (m, 2H).

Example 222:7-(Cyclopentylamino)-5-fluoro-2-(((trans-3-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-oneHydrochloride

Step 1: tert-Butyltrans-4-(acetylthio)-3-(trifluoromethyl)piperidine-1-carboxylate

Prepared from tert-butylcis-4-hydroxy-3-(trifluoromethyl)piperidine-1-carboxylate according tothe method described for Int-B3.

¹HNMR (400 MHz, CDCl₃) δ 5.23 (br s, 1H), 4.41 (br s, 1H), 3.94-3.89 (m,2H), 2.34 (s, 3H), 1.62-1.58 (m, 2H), 1.42 (s, 9H).

Step 2: tert-Butyltrans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-(trifluoromethyl)piperidine-1-carboxylate

Prepared from tert-butyltrans-4-(acetylthio)-3-(trifluoromethyl)piperidine-1-carboxylate andInt-A43 according to the method described for Example 202. LCMS: [M+H]⁺545.2.

Step 3:7-(Cyclopentylamino)-5-fluoro-2-(((trans-3-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-oneHydrochloride

Prepared from tert-butyltrans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-(trifluoromethyl)piperidine-1-carboxylateaccording to the method described for Example 48, step 2. LCMS: [M+H]⁺445.1;

¹H NMR (400 MHz, DMSO-d₆) δ 9.52-9.18 (m, 2H), 7.08 (br s, 1H),6.49-6.48 (m, 2H), 3.79-3.76 (m, 1H), 3.75-3.69 (m, 2H), 3.51-3.42 (m,1H), 3.39-3.23 (m, 2H), 3.14-2.91 (m, 3H), 2.37-2.28 (m, 1H), 2.02-1.92(m, 3H), 1.74-1.43 (m, 6H).

Example 223:7-(Cyclopentylamino)-5-fluoro-2-(((cis-4-fluoropyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-oneTrifluoroacetate

Step 1: tert-Butyl cis-3-(benzoylthio)-4-fluoropyrrolidine-1-carboxylate

To a solution of tert-butyltrans-3-fluoro-4-hydroxy-pyrrolidine-1-carboxylate (500 mg, 2.44 mmol,1.0 eq), benzenecarbothioic S-acid (673 mg, 4.87 mmol, 2.0 eq) and PPh₃(1.28 g, 4.87 mmol, 2.0 eq) in THF (15 mL) was added DEAD (849 mg, 4.87mmol, 2.0 eq) and the mixture was stirred at RT overnight under a N₂atmosphere. The mixture was diluted with water (80 mL) and extractedwith DCM (80 mL×3). The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified bycolumn chromatography (petroleum ether:EtOAc, 8:1, v/v) to afford thetitle compound (550 mg, 24%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.16-7.91 (m, 5H), 5.33 (d, J=52.8 Hz, 1H),4.40-4.23 (m, 1H), 3.92-3.54 (m, 3H), 3.26-3.18 (m, 1H), 1.42 (s, 9H).

Step 2: tert-Butylcis-3-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-4-fluoropyrrolidine-1-carboxylate

Prepared from Int-A43 and tert-butylcis-3-(benzoylthio)-4-fluoropyrrolidine-1-carboxylate according to themethod described for Example 202. LCMS: [M+H]⁺ 481.2.

Step 3:7-(Cyclopentylamino)-5-fluoro-2-(((cis-4-fluoropyrrolidin-3-yl)thio)methyl)quinazolin-4(3H)-oneTrifluoroacetate

Prepared from tert-butylcis-3-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-4-fluoropyrrolidine-1-carboxylateaccording to the method described for Example 48, step 2. Purificationby prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2 mm column, elutingwith a gradient of MeOH in water with 0.1% TFA, at a flow rate of 20mL/min) afforded the title compound. LCMS: [M+H]⁺ 381.1;

¹H NMR (400 MHz, DMSO-d₆) δ 11.8 (br s, 1H), 9.47 (br s, 1H), 9.27 (brs, 1H), 6.97 (br s, 1H), 6.43 (dd, J=14.0, 1.6 Hz, 1H), 6.38 (d, J=1.2Hz, 1H), 5.34 (d, J=54.8 Hz, 1H), 3.79-3.67 (m, 5H), 3.64-3.36 (m, 2H),3.09-2.96 (m, 1H), 2.00-1.88 (m, 2H), 1.74-1.63 (m, 2H), 1.63-1.51 (m,2H), 1.51-1.40 (m, 2H).

Example 224:7-(Cyclopentylamino)-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1: Methyl7-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-5-carboxylate

To a suspension of5-bromo-7-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one(300 mg, 0.80 mmol, 1.0 eq) in methanol (5 mL) was added Et₃N (163 mg,1.61 mmol, 2.0 eq) and PdCl₂(dppf) (59 mg, 0.08 mmol, 0.1 eq) and themixture was heated at 100° C. under a carbon monoxide atmosphere (50psi) for 15 h. After cooling to RT, the mixture was filtered and thefiltrate was dried over Na₂SO₄ and concentrated under reduced pressureto afford the title compound (230 mg, 81%) as a brown solid. LCMS:[M+H]⁺ 353.1.

Step 2:7-Fluoro-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of methyl7-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazoline-5-carboxylate(30 mg, 0.09 mmol, 1.0 eq) in THF (3 mL) was added sodium borohydride(10 mg, 0.26 mmol, 3.0 eq) and the mixture was stirred at RT for 2 h.The mixture was diluted with water (5 mL) and extracted with EtOAc (20mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-TLC (petroleum ether:EtOAc, 1:1, v/v) to afford the title compound(10 mg, 36%) as a white solid. LCMS: [M+H]⁺ 325.1.

Step 3:7-(Cyclopentylamino)-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from7-fluoro-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-oneand cyclopentanamine according to the method described for Example 126.LCMS: [M+H]⁺ 390.2;

¹HNMR (400 MHz, CD₃OD) δ 6.78 (d, J=2.4 Hz, 1H), 6.45 (s, 1H), 4.81 (s,2H), 3.82-3.76 (m, 3H), 3.56-3.54 (m, 2H), 3.36-3.29 (m, 2H), 2.95-2.87(m, 1H), 1.98-1.91 (m, 2H), 1.86-1.80 (m, 2H), 1.70-1.65 (m, 2H),1.61-1.55 (m, 2H), 1.52-1.45 (m, 4H).

Example 225:7-(cyclopentylamino)-5-(fluoromethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of7-(cyclopentylamino)-5-(hydroxymethyl)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one(100 mg, 0.26 mmol, 1.0 eq) in DCM (5 mL) at −78° C. under a N₂atmosphere was added Et₃N (52 mg, 0.51 mmol, 2.0 eq) and DAST (207 mg,1.28 mmol, 5.0 eq) and the mixture was stirred at −78° C. for 2 h. Afterwarming to RT, the reaction was quenched with water (5 mL) and themixture was extracted with DCM (20 mL×3). The combined organic layerswere dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2mm column, eluting with a gradient of ACN in water with 0.1% TFA, at aflow rate of 20 mL/min) to afford the title compound (3.5 mg, 3%) as awhite solid. LCMS: [M+H]⁺ 392.1; ¹HNMR (400 MHz, CD₃OD) δ 7.03 (s, 1H),6.58 (d, J=2.0 Hz, 1H), 5.92 (d, J=48.4 Hz, 2H), 3.96-3.90 (m, 3H),3.49-3.43 (m, 2H), 3.33 (2H, obscured by solvent peak), 3.12-3.06 (m,1H), 2.10-2.04 (m, 2H), 1.98-1.95 (m, 2H), 1.80-1.58 (m, 8H).

Example 226:7-(Cyclopentylamino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Step 1: tert-Butyl4-(((7-bromo-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

Prepared from Int-A48 and Int-B2 according to the method described forExample 202. LCMS: [M+H]⁺ 472.1.

Step 2: tert-Butyl4-(((7-bromo-3-(2-(tert-butoxy)-2-oxoethyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

To a solution of tert-butyl4-(((7-bromo-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate(790 mg, 1.67 mmol, 1.0 eq) in DMF (12 mL) was added chloromethyl2,2-dimethylpropanoate (302 mg, 2.01 mmol, 1.2 eq) and K₂CO₃ (347 mg,2.51 mmol, 1.5 eq) and the mixture was heated at 80° C. under a N₂atmosphere for 2 h. The mixture was diluted with water (60 mL) andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith water (20 mL×3), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (petroleumether:EtOAc, 15:1, v/v) to afford the title compound (550 mg, 56%) as abrown oil. LCMS: [M+H]⁺ 586.1.

Step 3: tert-Butyl4-(((3-(2-(tert-butoxy)-2-oxoethyl)-7-(cyclopentylamino)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

To a solution of tert-butyl4-(((7-bromo-3-(2-(tert-butoxy)-2-oxoethyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate(200 mg, 0.34 mmol, 1.0 eq) and cyclopentanamine (35 mg, 0.41 mmol, 1.2eq) in toluene (5 mL) under a N₂ atmosphere was added Cs₂CO₃ (167 mg,0.51 mmol, 1.5 eq), BINAP (42 mg, 0.07 mmol, 0.2 eq) and Pd₂(dba)₃ (31mg, 0.03 mmol, 0.1 eq) and the mixture was heated at 100° C. for 2 h.After cooling to RT, the mixture was diluted with water (30 mL) andextracted with EtOAc (20 mL×3). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by prep-TLC (petroleum ether:EtOAc, 3:1, v/v) to afford thetitle compound (90 mg, 45%) as a yellow solid. LCMS: [M+H]⁺ 591.3.

Step 4: tert-Butyl4-(((7-(cyclopentylamino)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

To a solution of tert-butyl4-(((3-(2-(tert-butoxy)-2-oxoethyl)-7-(cyclopentylamino)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate(90 mg, 0.15 mmol, 1.0 eq) in methanol (2 mL) was added 1 M NaOH (0.5mL) and the mixture was stirred at RT for 0.5 h. The mixture was dilutedwith water (30 mL), extracted with EtOAc (20 mL×2) and the combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by prep-TLC (DCM:MeOH, 20:1, v/v) toafford the title compound (66 mg, 91%) as a white solid. LCMS: [M+H]⁺477.2.

Step 5:7-(Cyclopentylamino)-6-fluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Prepared from tert-butyl4-(((7-(cyclopentylamino)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylateaccording to the method described for Example 48, step 2. LCMS: [M+H]⁺377.1;

¹H NMR (400 MHz, DMSO-d₆) δ 9.04-8.90 (m, 2H), 7.58 (d, J=11.6 Hz, 1H),6.92 (d, J=7.2 Hz, 1H), 6.68 (br s, 1H), 3.85-3.78 (m, 3H), 3.24-3.14(m, 3H), 2.94-2.86 (m, 2H), 2.17-2.13 (m, 2H), 2.03-1.95 (m, 2H),1.71-1.53 (m, 8H).

Example 227:7-(Cyclopentylamino)-5-fluoro-2-(((trans-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-onebis trifluoroacetate

Step 1: tert-Butylcis-4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylate

Prepared from tert-butyl4-oxo-2-(trifluoromethyl)piperidine-1-carboxylate according to theprocedure described in WO201391773.

Step 2: tert-Butylcis-4-((methylsulfonyl)oxy)-2-(trifluoromethyl)piperidine-1-carboxylate

Prepared from tert-butylcis-4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylate according tothe procedure described for Int-B3 step 1. LCMS: [M+H]⁺ 348.1.

Step 3: tert-Butyltrans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-2-(trifluoromethyl)piperidine-1-carboxylate

Prepared from Int-C12 and tert-butylcis-4-((methylsulfonyl)oxy)-2-(trifluoromethyl)piperidine-1-carboxylateaccording to the method described for Example 210, step 3. LCMS:[M+H]⁺545.2.

Step 4:7-(Cyclopentylamino)-5-fluoro-2-(((trans-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-onebis trifluoroacetate

Prepared from tert-butyltrans-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-2-(trifluoromethyl)piperidine-1-carboxylateaccording to the method described for Example 48, step 2. Purificationby prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2 mm column, elutingwith a gradient of MeOH in water with 0.1% TFA, at a flow rate of 20mL/min) afforded the title compound. LCMS: [M+H]⁺ 445.1;

¹H NMR (400 MHz, CD₃OD) δ 6.49-6.43 (m, 2H), 4.52-4.43 (m, 1H),3.87-3.81 (m, 1H), 3.69-3.65 (m, 1H), 3.49-3.40 (m, 2H), 2.71 (s, 2H),2.41-2.33 (m, 1H), 2.27-2.16 (m, 2H), 2.15-2.00 (m, 3H), 1.82-1.53 (m,6H).

¹⁹F NMR (400 MHz, CD₃OD) δ −75.9, −76.3, −77.3, −113.1.

Example 228:7-(Cyclopentylamino)-5-fluoro-2-(((cis-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-oneHydrochloride

Step 1: tert-Butyltrans-4-((4-nitrobenzoyl)oxy)-2-(trifluoromethyl)piperidine-1-carboxylate

To a solution of tert-butylcis-4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylate (500 mg, 1.86mmol, 1.0 eq), 4-nitrobenzoic acid (621 mg, 3.71 mmol, 2.0 eq) andtriphenylphosphine (974 mg, 3.71 mmol, 2.0 eq) in THF (15 mL) at 0° C.under a N₂ atmosphere was added DEAD (647 mg, 3.71 mmol, 2.0 eq) and themixture was allowed to warm to RT and stirred overnight. The mixture wasdiluted with water (20 mL), extracted with EtOAc (15 mL×3) and thecombined organic layers were washed with water (20 mL), brine (20 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (petroleum ether:EtOAc, 20:1, v/v)to afford the title compound (430 mg, 55%) as a white solid. LCMS:[M+H]⁺ 419.1.

Step 2: tert-Butyltrans-4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylate

A mixture of tert-butyltrans-4-(4-nitrobenzoyl)oxy-2-(trifluoromethyl)piperidine-1-carboxylate(400 mg, 0.96 mmol, 1.0 eq) and 2 M NaOH (8.0 mL) in methanol (16 mL)was stirred at 20° C. for 2 h. The mixture was diluted with water (30mL) and extracted with EtOAc (25 mL×3). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄ and concentrated underreduced pressure to afford the title compound (200 mg, 78%) as an offwhite solid.

¹HNMR (400 MHz, DMSO-d₆) δ 4.96 (br s, 1H), 4.93-4.73 (m, 1H), 4.10-3.96(m, 1H), 3.77-3.65 (m, 1H), 2.94-2.69 (m, 1H), 2.06-1.98 (m, 1H),1.88-1.78 (m, 1H), 1.58-1.44 (m, 1H), 1.40 (s, 9H), 1.24-1.65 (m, 1H).

Step 3: tert-Butyltrans-4-((methylsulfonyl)oxy)-2-(trifluoromethyl)piperidine-1-carboxylate

Prepared from tert-butyltrans-4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylate according tothe procedure described for Int-B3 step 1. LCMS: [M+H]⁺ 348.1.

Step 4: tert-Butylcis-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-2-(trifluoromethyl)piperidine-1-carboxylate

Prepared from Int-C12 and tert-butyltrans-4-((methylsulfonyl)oxy)-2-(trifluoromethyl)piperidine-1-carboxylateaccording to the method described for Example 210, step 3. LCMS: [M+H]⁺545.2.

Step 5:7-(Cyclopentylamino)-5-fluoro-2-(((cis-2-(((cis-2-(trifluoromethyl)piperidin-4-yl)thio)methyl)quinazolin-4(3H)-oneHydrochloride

Prepared from tert-butylcis-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-2-(trifluoromethyl)piperidine-1-carboxylateaccording to the method described for Example 48, step 2. LCMS: [M+H]⁺445.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.1 (br s, 1H), 10.0 (br s, 2H), 7.07 (brs, 1H), 6.53-6.40 (m, 2H), 4.40-4.31 (m, 1H), 3.78-3.69 (m, 3H),3.43-3.36 (m, 1H), 3.18-3.04 (m, 2H), 2.54-2.52 (m, 1H), 2.21-2.13 (m,1H), 1.99-1.91 (m, 2H), 1.72-1.54 (m, 6H), 1.51-1.42 (m, 2H).

Example 229:7-(Cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-oneHydrochloride

Step 1: tert-Butyl4-(((7-chloro-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)methyl)thio)piperidine-1-carboxylate

Prepared from Int-A44 and Int-B2 according to the method described forExample 202. LCMS: [M+H]⁺ 411.1.

Step 2: tert-Butyl4-(((7-(cyclopropylmethoxy)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)methyl)thio)piperidine-1-carboxylate

To a solution of cyclopropylmethanol (53 mg, 0.73 mmol, 5.5 eq) in THF(3 mL) at 0° C. was added NaH (60% w/w dispersion in oil, 58 mg, 1.46mmol, 10 eq) portion-wise and the mixture was stirred for 30 min. Asolution of tert-butyl4-(((7-chloro-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)methyl)thio)piperidine-1-carboxylate(60 mg, 0.15 mmol, 1.0 eq) in THF (0.5 mL) was then added and themixture was allowed to warm to RT and stirred for 1 h. The mixture wascooled to 0° C., diluted with water (10 mL) and extracted with EtOAc (15mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by prep-TLC (DCM:MeOH, 60:1, v/v) to afford the title compound(30 mg, 46%) as a light-yellow solid. LCMS: [M+H]⁺ 447.1.

Step 3:7-(Cyclopropylmethoxy)-2-((piperidin-4-ylthio)methyl)pyrido[2,3-d]pyrimidin-4(3H)-oneHydrochloride

Prepared from tert-butyl4-(((7-(cyclopropylmethoxy)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)methyl)thio)piperidine-1-carboxylateaccording to the method described for Example 48, step 2. LCMS: [M+H]⁺347.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.5 (br s, 1H), 8.60 (br s, 2H), 8.29 (d,J=8.8 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.21 (d, J=7.2 Hz, 2H), 3.72 (s,2H), 3.27-3.20 (m, 2H), 3.13-3.05 (m, 1H), 2.96-2.87 (m, 2H), 2.17-2.07(m, 2H), 1.69-1.59 (m, 2H), 1.32-1.23 (m, 1H), 0.60-0.55 (m, 2H),0.40-0.32 (m, 2H).

Example 230:7-((Cyclobutylmethyl)amino)-6-methoxy-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Step 1: tert-Butyl4-(((7-bromo-6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

Prepared from Int-A45 and Int-B2 according to the method described forExample 202. LCMS: [M+H]⁺ 484.1.

Step 2: tert-Butyl4-(((7-((cyclobutylmethyl)amino)-6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

Prepared from tert-butyl4-(((7-bromo-6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylateand cyclobutylmethanamine according to the method described for Example226, step 2, 3 and 4. LCMS: [M+H]⁺ 489.2.

Step 3:7-((Cyclobutylmethyl)amino)-6-methoxy-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Prepared from tert-butyl4-(((7-((cyclobutylmethyl)amino)-6-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylateaccording to the method described for Example 48, step 2. LCMS: [M+H]⁺389.1;

¹H NMR (400 MHz, DMSO-d₆) δ 13.5 (br s, 1H), 9.11-8.88 (m, 2H), 7.25 (s,1H), 6.88 (s, 1H), 6.64 (br s, 1H), 3.96 (s, 2H), 3.93 (s, 3H),3.28-3.18 (m, 5H), 2.94-2.85 (m, 2H), 2.69-2.60 (m, 1H), 2.22-2.12 (m,2H), 2.07-1.95 (m, 2H), 1.90-1.80 (m, 2H), 1.77-1.60 (m, 4H).

Example 231:7-((2,2-Difluorocyclopentyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1:7-Bromo-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from Int-A46 and Int B1 according to the method described forExample 202. LCMS: [M+H]⁺ 373.0.

Step 2:7-((2,2-Difluorocyclopentyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from7-bromo-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-oneand 2,2-difluorocyclopentan-1-amine according to the method describedfor Example 226, step 2, 3 and 4. LCMS: [M+H]⁺ 414.1;

¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 6.93 (d, J=8.0 Hz, 1H),6.57-6.54 (m, 2H), 4.22-4.15 (m, 1H), 3.82-3.79 (m, 2H), 3.55 (s, 2H),3.36-3.27 (m, 2H), 3.06-3.00 (m, 1H), 2.25-2.03 (m, 3H), 1.89-1.86 (m,2H), 1.78-1.72 (m, 2H), 1.65-1.60 (m, 1H), 1.48-1.38 (m, 2H).

Example 232:7-(Cyclopentylamino)-5,6-difluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Step 1: tert-Butyl4-(((7-(cyclopentylamino)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylate

Prepared from Int-A47 and Int-B2 according to the method described forExample 202. LCMS: [M+H]⁺ 495.2.

Step 2:7-(Cyclopentylamino)-5,6-difluoro-2-((piperidin-4-ylthio)methyl)quinazolin-4(3H)-oneHydrochloride

Prepared from tert-butyl4-(((7-(cyclopentylamino)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)piperidine-1-carboxylateaccording to the method described for Example 48, step 2. LCMS: [M+H]⁺395.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (br s, 1H), 8.95 (br s, 1H), 8.83 (brs, 1H), 6.81 (br s, 1H), 6.63 (d, J=7.2 Hz, 1H), 3.91-3.82 (m, 1H), 3.67(s, 2H), 3.21-3.17 (m, 2H), 3.16-3.04 (m, 1H), 2.95-2.85 (m, 2H),2.19-2.06 (m, 2H), 2.04-1.91 (m, 2H), 1.78-1.53 (m, 8H).

Example 233:5-Fluoro-7-((trans-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-oneTrifluoroacetate and Example 234:5-Fluoro-7-((cis-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-oneTrifluoroacetate

Step 1:7-((1,4-Dioxaspiro[4,5]decan-8-yl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from7-bromo-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-oneand 1,4-dioxaspiro[4.5]decan-8-amine according to the method describedfor Example 226, step 2, 3, 4. LCMS: [M+H]⁺ 450.2.

Step 2:5-Fluoro-7-((4-oxocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from7-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-oneaccording to the method described for Example 21, step 3. LCMS: [M+H]⁺406.1.

Step 3:5-Fluoro-7-((4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of5-fluoro-7-((4-oxocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one(30 mg, 0.07 mmol, 1.0 eq) in methanol (2 mL) was added morpholine (32mg, 0.37 mmol, 5.0 eq) and the mixture was stirred at RT for 30 min.NaCNBH₃ (24 mg, 0.38 mmol, 5.0 eq) was then added and the mixture wasstirred at RT overnight. The reaction was quenched with a saturatedaqueous NaHCO₃ solution (20 mL) and the mixture was extracted with EtOAc(30 mL×2). The combined organic layers were washed with brine (40 mL),dried over Na₂SO₄ and concentrated under reduced pressure to afford thetitle compound (10 mg, 28%) as a white solid. LCMS: [M+H]⁺ 477.2.

Step 4:5-Fluoro-7-((trans-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-oneTrifluoroacetate and5-Fluoro-7-((cis-4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-onetrifluoroacetate

5-Fluoro-7-((4-morpholinocyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-onefurther purified by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2 mmcolumn, eluting with a gradient of ACN in water with 0.1% TFA, at a flowrate of 20 mL/min) to afford the title compounds.

Example 233

LCMS: [M+H]⁺ 477.2;

¹H NMR (400 MHz, CD₃OD) δ 6.63-6.58 (m, 2H), 4.10 (d, J=12.0 Hz, 2H),3.93-3.89 (m, 2H), 3.82-3.73 (m, 2H), 3.51-3.41 (m, 5H), 3.35-3.31 (m,2H), 3.26-3.20 (m, 3H), 3.09-3.04 (m, 1H), 2.28-2.25 (m, 4H), 1.98-1.93(m, 2H), 1.78-1.69 (m, 2H), 1.63-1.54 (m, 2H), 1.49-1.37 (m, 2H).

Example 234

LCMS: [M+H]⁺ 477.2;

¹H NMR (400 MHz, CD₃OD) δ 6.63-6.58 (m, 2H), 4.10 (d, J=13.2 Hz, 2H),3.93-3.90 (m, 2H), 3.83-3.77 (m, 3H), 3.51-3.41 (m, 4H), 3.35-3.31 (m,2H), 3.27-3.22 (m, 3H), 3.10-3.03 (m, 1H), 2.15-2.12 (m, 2H), 2.05-2.02(m, 2H), 1.97-1.94 (m, 2H), 1.88-1.77 (m, 4H), 1.63-1.53 (m, 2H).

Example 235:7-(Cyclopropylmethoxy)-5-fluoro-2-(((trans-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

To a solution of Int-A49 (300 mg, 1.06 mmol, 1.0 eq) in THF (5 mL) undera N₂ atmosphere was added Int-B11 (168 mg, 1.27 mmol, 1.2 eq) and 2 MNaOH (2 mL) and the mixture was stirred at RT overnight. The mixture waspoured into water (30 mL) and extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine (30 mL), dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby C18 reverse phase column (Biotage, 40% ACN in water) to afford thetitle compound (130 mg, 32%) as a white solid. LCMS: [M+H]⁺ 379.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.1 (s, 1H), 6.89-6.86 (m, 2H), 4.52 (d,J=4.4 Hz, 1H), 3.96 (d, J=7.2 Hz, 2H), 3.57 (s, 2H), 3.40-3.38 (m, 1H),2.74-2.67 (m, 1H), 1.97-1.94 (m, 2H), 1.82-1.80 (m, 2H), 1.28-1.11 (m,5H), 0.60-0.58 (m, 2H), 0.37-0.33 (m, 2H).

Example 236:5-Fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from Int-A50 and Int-B1 according to the method described forExample 202. LCMS: [M+H]⁺ 409.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (s, 1H), 6.95-6.84 (m, 2H), 3.99 (d,J=6.4 Hz, 2H), 3.92-3.77 (m, 4H), 3.61 (s, 2H), 3.38-3.32 (m, 2H),3.31-3.27 (m, 2H), 3.10-3.00 (m, 1H), 2.08-1.97 (m, 1H), 1.93-1.84 (m,2H), 1.72-1.63 (m, 2H), 1.51-1.27 (m, 4H).

Example 237:7-(Cyclobutylmethoxy)-5-methyl-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from Int-A51 and Int-B1 according to the method described forExample 202. LCMS: [M+H]⁺ 375.1;

¹H NMR (400 MHz, DMSO-d₆) δ 11.9 (s, 1H), 6.85 (s, 1H), 6.82 (s, 1H),4.05 (d, J=6.4 Hz, 2H), 3.83-3.80 (m, 2H), 3.60 (s, 2H), 3.35-3.32 (m,2H), 3.08-3.01 (m, 1H), 2.77-2.70 (m, 1H), 2.70 (s, 3H), 2.11-2.04 (m,2H), 1.95-1.79 (m, 6H), 1.49-1.40 (m, 2H).

Example 238:5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one

Prepared from Int-A52 and Int-B1 according to the method described forExample 202. LCMS: [M+H]⁺ 395.0;

¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (s, 1H), 6.94-6.84 (m, 2H), 4.10-4.00(m, 2H), 3.84-3.72 (m, 4H), 3.69-3.62 (m, 1H), 3.60 (s, 2H), 3.55-3.48(m, 1H), 3.37-3.34 (m, 1H), 3.30-3.27 (m, 1H), 3.08-2.99 (m, 1H),2.70-2.63 (m, 1H), 2.07-1.96 (m, 1H), 1.92-1.83 (m, 2H), 1.70-1.62 (m,1H), 1.48-1.37 (m, 2H).

Example 239:(R)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-oneand(S)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one

Example 238 was further purified by chiral prep-HPLC (Chiralpak IE-3, 3μm, 0.46×5 cm column, eluting with a gradient of hexane:DCM (0.1%DEA):MeOH 50:50 at a flow rate of 1.0 mL/min) to afford the titlecompounds with retention times of 2.09 minutes (239a) and 3.35 minutes(239b).

Example 239a

LCMS: [M+H]⁺ 395.2;

¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (s, 1H), 6.91-6.87 (m, 2H), 4.11-4.01(m, 2H), 3.84-3.75 (m, 4H), 3.69-3.63 (m, 1H), 3.62 (s, 2H), 3.56-3.52(m, 1H), 3.34-3.33 (m, 1H), 3.30-3.27 (m, 1H), 3.06-2.99 (m, 1H),2.68-2.63 (m, 1H), 2.04-1.96 (m, 1H), 1.91-1.88 (m, 2H), 1.70-1.65 (m,1H), 1.49-1.40 (m, 2H).

Example 239b

LCMS: [M+H]⁺ 395.2;

¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (s, 1H), 6.88-6.82 (m, 2H), 4.10-4.02(m, 2H), 3.84-3.75 (m, 4H), 3.69-3.63 (m, 1H), 3.62 (s, 2H), 3.56-3.52(m, 1H), 3.34-3.33 (m, 1H), 3.30-3.27 (m, 1H), 3.09-3.03 (m, 1H),2.68-2.63 (m, 1H), 2.04-1.96 (m, 1H), 1.91-1.88 (m, 2H), 1.70-1.65 (m,1H), 1.49-1.42 (m, 2H).

Example 240:7-(Cyclopentylamino)-5-fluoro-2-(((trans-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1: tert-Butyl 3-fluoro-5-hydroxyazepane-1-carboxylate

Prepared from 1,3-dichloropropan-2-one according to procedure describedin US2015197493.

Step 2: tert-Butyl 3-fluoro-5-((methylsulfonyl)oxy)azepane-1-carboxylate

Prepared from tert-butyl 3-fluoro-5-hydroxyazepane-1-carboxylateaccording to the method described for Int-B3, step 1. LCMS: [M+H]⁺312.1.

Step 3: tert-Butyl5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoroazepane-1-carboxylate

Prepared from Int-C12 and tert-butyl3-fluoro-5-((methylsulfonyl)oxy)azepane-1-carboxylate according to themethod described for Example 210, step 3. LCMS: [M+H]⁺ 509.2.

Step 4: tert-Butyltrans-5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoroazepane-1-carboxylateand tert-Butylcis-5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoroazepane-1-carboxylate

tert-Butyl5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoroazepane-1-carboxylatewas further purified by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2mm column, eluting with a gradient of MeOH in water with 0.1% TFA, at aflow rate of 20 mL/min) to afford the titled trans isomer, LCMS: [M+H]⁺509.2 and cis isomer, LCMS: [M+H]⁺ 509.2. (Cis and trans assignmentswere made arbitrarily).

Step 5:7-(Cyclopentylamino)-5-fluoro-2-(((trans-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from tert-butyltrans-5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoroazepane-1-carboxylateaccording to the method described for Example 48, step 2. The crudeproduct was partitioned between a saturated aqueous Na₂CO₃ solution (10mL) and EtOAc (30 mL). The layers were separated and the organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-TLC (DCM/MeOH, 10:1, v/v) to afford thetitle compound. LCMS: [M+H]⁺ 409.1;

¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 6.85 (d, J=6.0 Hz, 1H), 6.42(d, J=13.6 Hz, 1H), 6.36 (s, 1H), 4.96 (d, J=43.6 Hz, 1H), 3.78-3.75 (m,1H), 3.57 (s, 2H), 3.17-2.85 (m, 4H), 2.40-2.30 (m, 1H), 2.17-2.08 (m,2H), 2.00-1.87 (m, 3H), 1.76-1.68 (m, 3H), 1.58-1.54 (m, 2H), 1.47-1.42(m, 2H).

Example 241:7-(Cyclopentylamino)-5-fluoro-2-(((cis-6-fluoroazepan-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from tert-butylcis-5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-3-fluoroazepane-1-carboxylateaccording to the method described for Example 48, step 2. The crudeproduct was partitioned between a saturated aqueous Na₂CO₃ solution (10mL) and EtOAc (30 mL). The layers were separated and the organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by prep-TLC (DCM/MeOH, 10:1, v/v) to afford thetitle compound. LCMS: [M+H]⁺ 409.1;

¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 6.86 (d, J=6.0 Hz, 1H), 6.42(d, J=14.0 Hz, 1H), 6.36 (s, 1H), 4.96 (d, J=48.0 Hz, 1H), 3.78-3.75 (m,1H), 3.56 (s, 2H), 3.11-3.01 (m, 4H), 2.76-2.70 (m, 1H), 2.43-2.34 (m,1H), 2.05-1.93 (m, 4H), 1.73-1.62 (m, 3H), 1.58-1.54 (m, 2H), 1.47-1.42(m, 2H).

Example 242:2-((((cis)-6-(Aminomethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-onebis hydrochloride

Step 1: (3,4-Dihydro-2H-pyran-2-yl)methanol

Prepared from 3,4-dihydro-2H-pyran-2-carbaldehyde according toliterature Bioorg. Med. Chem. 2006, 14, 3953.

Step 2: (3,4-Dihydro-2H-pyran-2-yl)methyl methanesulfonate

Prepared from (3,4-dihydro-2H-pyran-2-yl)methanol according to themethod described for Int B3, step 1.

¹H NMR (400 MHz, CDCl₃) δ 6.36 (d, J=6.0 Hz, 1H), 4.80-4.72 (m, 1H),4.32-4.29 (m, 2H), 4.14-4.06 (m, 1H), 3.07 (s, 3H), 2.18-2.08 (m, 1H),2.08-2.03 (m, 1H), 1.91-1.84 (m, 1H), 1.78-1.67 (m, 1H).

Step 3: 2-((3,4-Dihydro-2H-pyran-2-yl)methyl)isoindoline-1,3-dione

To a mixture of 3,4-dihydro-2H-pyran-2-ylmethyl methanesulfonate (500mg, 2.6 mmol, 1.0 eq) in DMSO (3 mL) was added potassium phthalimide(578 mg, 3.12 mmol, 1.2 eq) and the mixture was heated at 90° C. for 16h. After cooling to RT, the mixture was poured into water (20 mL) andextracted with EtOAc (10 mL×3). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (petroleumether/EtOAc, 1:0 to 10:1, v/v) to afford the title compound (350 mg,55%) as a white solid. LCMS: [M+H]⁺ 244.0.

Step 4: (3,4-Dihydro-2H-pyran-2-yl)methanamine

To a mixture of 2-(3,4-dihydro-2H-pyran-2-ylmethyl)isoindoline-1,3-dione(500 mg, 2.06 mmol) in methanol (5 mL) at 0° C. was added hydrazinehydrate (0.25 mL, 4.11 mmol, 2.0 eq) and the mixture was heated at 50°C. for 16 h. The mixture was concentrated under reduced pressure and theresidue was triturated with DCM (20 mL) and filtered. The filtrate wasconcentrated under reduced pressure to afford the title compound (230mg, 99%) as a light yellow solid, which was used in next step directly.

Step 5: tert-Butyl ((3,4-dihydro-2H-pyran-2-yl)methyl)carbamate

To a solution of (3,4-dihydro-2H-pyran-2-yl)methanamine (230 mg, 2.03mmol, 1.0 eq) in DCM (4 mL) at RT was added Et₃N (0.34 mL, 2.44 mmol,2.2 eq) followed by di-tert-butyl dicarbonate (532 mg, 2.44 mmol, 2.2eq) and the mixture was stirred at RT for 5 h. The mixture was dilutedwith DCM (10 mL) and washed with water (5 mL). The organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (petroleum ether:EtOAc, 1:0 to10:1, v/v) to afford the title compound (200 mg, 46%) as a colorlessoil.

¹H NMR (400 MHz, CDCl₃) δ 6.34 (d, J=6.0 Hz, 1H), 4.89 (br s, 1H),4.73-4.65 (m, 1H), 3.91-3.81 (m, 1H), 3.47-3.38 (m, 1H), 3.25-3.11 (m,1H), 2.16-2.03 (m, 1H), 2.01-1.92 (m, 1H), 1.87-1.77 (m, 1H), 1.68-1.59(m, 1H), 1.45 (s, 9H).

Step 6: tert-Butyl ((5-hydroxytetrahydro-2H-pyran-2-yl)methyl)carbamate

To a solution of tert-butyl ((3,4-dihydro-2H-pyran-2-yl)methyl)carbamate(800 mg, 3.75 mmol, 1.0 eq) in THF (3 mL) at 0° C. was added a 1 MBH₃/THF solution (18.8 mL, 18.8 mmol, 5.0 eq) dropwise and the mixturewas allowed to warm to RT and stirred for 16 h. 3 M NaOH (6 mL) and H₂O₂(30% aqueous solution, 8 mL) were then added dropwise and the mixturewas heated at 55° C. for 1 h. After cooling to 0° C., the reaction wasquenched with water (15 mL) and the mixture was extracted with EtOAc (30mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure to afford the title compound (700mg, 80%) as colorless oil, which was used in next step directly withoutfurther purification.

Step 7:trans-6-(((tert-Butoxycarbonyl)amino)methyl)tetrahydro-2H-pyran-3-ylmethanesulfonate andcis-6-(((tert-Butoxycarbonyl)amino)methyl)tetrahydro-2H-pyran-3-ylmethanesulfonate

To a solution of tert-butyl((5-hydroxytetrahydro-2H-pyran-2-yl)methyl)carbamate (700 mg, 3.03 mmol,1.0 eq) in DCM (10 mL) was added Et₃N (0.63 mL, 4.54 mmol, 1.5 eq)followed by methanesulfonyl chloride (0.28 mL, 3.63 mmol, 1.2 eq) andthe mixture was stirred at RT for 2 h. The mixture was diluted withwater (30 mL) and extracted with EtOAc (50 mL×3). The combined organicextracts were dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by column chromatography (petroleumether:EtOAc, 5:1 to 1:1, v/v) to afford the titled trans isomer (150 mg,16%) and cis isomer (200 mg, 21%) as white solids.

Trans isomer: ¹H NMR (400 MHz, CDCl₃) δ 4.86 (br s, 1H), 4.66-4.59 (m,1H), 4.18-4.05 (m, 1H), 3.40-3.30 (m, 2H), 3.02 (s, 3H), 3.02-2.93 (m,1H), 2.32-2.08 (m, 1H), 1.84-1.66 (m, 2H), 1.48-1.38 (m, 10H), 1.31-1.15(m, 1H).

Cis isomer: ¹H NMR (400 MHz, CDCl₃) δ 4.77 (br s, 1H), 4.20-4.07 (m,1H), 3.65-3.60 (m, 1H), 3.48-3.32 (m, 2H), 3.07 (s, 3H), 3.06-2.98 (m,1H), 2.25-2.18 (m, 1H), 1.89-1.63 (m, 4H), 1.44 (s, 9H).

Step 8: tert-Butyl((cis-5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)tetrahydro-2H-pyran-2-yl)methyl)carbamate

Prepared from Int-C12 andtrans-6-(((tert-butoxycarbonyl)amino)methyl)tetrahydro-2H-pyran-3-ylMethanesulfonate according to the method described for Example 210, step3. LCMS: [M+H]⁺ 507.1.

Step 9:2-((((cis)-6-(Aminomethyl)tetrahydro-2H-pyran-3-yl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-onebis hydrochloride

Prepared from tert-butyl((cis-5-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)tetrahydro-2H-pyran-2-yl)methyl)carbamateaccording to the method described for Example 48, step 2. LCMS: [M+H]⁺407.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.0 (br s, 1H), 7.89 (br s, 4H), 7.09 (brs, 1H), 6.54-6.38 (m, 2H), 3.87-3.84 (m, 1H), 3.80-3.71 (m, 3H), 3.22(s, 1H), 2.91 (m, 2H), 2.76 (m, 2H), 1.97-1.85 (m, 3H), 1.73-1.35 (m,9H).

Example 243:2-(((trans-4-(Aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-oneTrifluoroacetate

Step 1: (((4-Methylenecyclohexyl)oxy)methyl) benzene

To a mixture of methyl (triphenyl)phosphonium bromide (10.5 g, 29.4mmol, 1.5 eq) in anhydrous THF (70 mL) at −10° C. under N₂ was addedn-BuLi (2.5 M solution in hexanes, 11.0 mL, 27.4 mmol, 1.4 eq) and themixture was stirred at −10° C. for 1 h. A solution of4-benzyloxycyclohexanone (4.0 g, 19.6 mmol, 1.0 eq) in THF (10 mL) wasthen added dropwise and the mixture was allowed to warm to RT andstirred for 3 h. The reaction was quenched with water (100 mL) and themixture was extracted with EtOAc (80 mL×3). The combined organicextracts were washed with brine (50 mL), dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (petroleum ether/EtOAc, 1:0 to 20:1, v/v) to afford thetitle compound (3.4 g, 86%) as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ7.29-7.17 (m, 5H), 4.56 (s, 2H), 4.49 (s, 2H), 3.49-3.45 (m, 1H),2.33-2.27 (m, 2H), 2.00-1.94 (m, 2H), 1.85-1.82 (m, 2H), 1.58-1.49 (m,2H).

Step 2: (((4-(Bromomethyl)-4-fluorocyclohexyl)oxy)methyl)benzene

To a solution of (((4-methylenecyclohexyl)oxy)methyl)benzene (2.4 g,11.9 mmol, 1.0 eq) in DCM (24 mL) at 0° C. was added triethylaminetrihydrofluoride (2.9 mL, 17.8 mmol, 1.5 eq) and NBS (2.32 g, 13.1 mmol,1.1 eq) and the mixture was allowed to warm to RT and stirred for 5 h.The mixture was diluted with DCM (80 mL) and washed with 0.5 M HCl (20mL) and brine (20 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to afford the title compound (3.55g, 99%) as light yellow oil, which was used directly in the next stepwithout further purification.

Step 3: (((cis-4-(Azidomethyl)-4-fluorocyclohexyl)oxy)methyl)benzene and(((trans-4-(Azidomethyl)-4-fluorocyclohexyl)oxy)methyl) benzene

To the solution of(((4-(bromomethyl)-4-fluorocyclohexyl)oxy)methyl)benzene (3.55 g, 11.8mmol, 1.0 eq) in DMSO (20 mL) was added KI (2.94 g, 17.7 mmol, 1.5 eq)and NaN₃ (1.15 g, 17.7 mmol, 1.5 eq) and the mixture was heated at 120°C. for 16 h. The mixture was poured into ice-water (20 mL) and extractedwith DCM (100 mL×3). The combined organic layers were washed with brine(50 mL), dried over dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography(petroleum:EtOAc, 1:0 to 10:1, v/v) to afford the titled trans isomer(1.5 g, 48%) and the cis isomer (700 mg, 23%) as light yellow solids.(Cis and trans assignments were made arbitrarily).

Cis isomer ¹HNMR (400 MHz, CDCl₃) δ 7.35-7.33 (m, 5H), 4.62-4.54 (m,1H), 4.51 (s, 2H), 3.33-3.28 (m, 2H), 2.20-1.76 (m, 8H).

Trans isomer ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.34 (m, 5H), 4.58 (s, 2H),3.41-3.27 (m, 3H), 2.10-2.07 (m, 2H), 2.06-2.05 (m, 2H), 2.04-2.02 (m,2H), 1.78-1.48 (m, 2H).

Step 4: cis-4-(Aminomethyl)-4-fluorocyclohexan-1-ol

The mixture of(((cis-4-(azidomethyl)-4-fluorocyclohexyl)oxy)methyl)benzene (1 g, 3.8mmol, 1.0 eq) and 10% Pd(OH)₂/C (200 mg) in methanol (10 mL) was heatedat 50° C. under a H₂ atmosphere (100 atm) for 24 h. After cooling to RT,the mixture was filtered through Celite and the filtrate wasconcentrated under reduced pressure to afford the title compound (500 g,90%) as light yellow oil, which was used for the next step directlywithout further purification.

Step 5: tert-Butyl(((trans)-1-fluoro-4-hydroxycyclohexyl)methyl)carbamate

Prepared from cis-4-(aminomethyl)-4-fluorocyclohexan-1-ol according tothe method described for Example 242, step 5 and used directly in thenext step.

Step 6: cis-4-(((tert-Butoxycarbonyl)amino)methyl)-4-fluorocyclohexylMethanesulfonate

Prepared from tert-butyl(((trans)-1-fluoro-4-hydroxycyclohexyl)methyl)carbamate according to themethod described for Int-B3, step 1. LCMS: [M+H]⁺ 326.1.

Step 7: tert-Butyl(((cis)-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-1-fluorocyclohexyl)methyl)carbamate

Prepared from Int-C12 andcis-4-(((tert-butoxycarbonyl)amino)methyl)-4-fluorocyclohexylmethanesulfonate according to the method described for Example 210, step3. LCMS: [M+H]⁺523.1.

Step 8:2-(((trans-4-(Aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-oneTrifluoroacetate

Prepared from tert-butyl(((cis)-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-1-fluorocyclohexyl)methyl)carbamateaccording to the method described for Example 48, step 2. Purificationby prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2 mm column, elutingwith a gradient of MeOH in water with 0.1% TFA, at a flow rate of 20mL/min) afforded the title compound. LCMS: [M+H]⁺ 423.1;

¹H NMR (400 MHz, DMSO-d₆) δ 11.7 (br s, 1H), 7.96 (br s, 3H), 6.86 (brs, 1H), 6.42 (dd, J=13.8, 2.2 Hz, 1H), 6.35 (d, J=2.1 Hz, 1H), 3.79 (m,1H), 3.53 (s, 2H), 3.24-3.05 (m, 3H), 2.01-1.87 (m, 4H), 1.86-1.54 (m,9H), 1.49-1.43 (m, 3H).

Example 244:2-(((cis-4-(Aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-oneTrifluoroacetate

Step 1: trans-4-(Aminomethyl)-4-fluorocyclohexan-1-ol

Prepared from(((trans-4-(azidomethyl)-4-fluorocyclohexyl)oxy)methyl)benzene accordingto the method described for Example 243, step 4 and used directly in thenext step.

Step 2: tert-Butyl ((cis-1-fluoro-4-hydroxycyclohexyl)methyl)carbamate

Prepared from trans-4-(aminomethyl)-4-fluorocyclohexan-1-ol according tothe method described for Example 242, step 5.

¹HNMR (400 MHz, CDCl₃) δ 4.81 (br s, 1H), 4.05-3.98 (m, 1H), 3.36-3.29(m, 2H), 1.87-1.78 (m, 2H), 1.78-1.58 (m, 2H), 1.55-1.49 (m, 2H), 1.47(s, 9H).

Step 3: trans-4-(((tert-Butoxycarbonyl)amino)methyl)-4-fluorocyclohexylMethanesulfonate

Prepared from tert-butyl((cis-1-fluoro-4-hydroxycyclohexyl)methyl)carbamate according to themethod described for Int-B3, step 1. LCMS: [M+H]⁺ 326.1.

Step 4: tert-Butyl(((trans)-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-1-fluorocyclohexyl)methyl)carbamate

Prepared from Int-C12 andtrans-4-(((tert-butoxycarbonyl)amino)methyl)-4-fluorocyclohexylmethanesulfonate according to the method described for Example 210, step3. LCMS: [M+H]⁺523.1.

Step 5:2-(((cis-4-(Aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclopentylamino)-5-fluoroquinazolin-4(3H)-oneTrifluoroacetate

Prepared from tert-butyl(((trans)-4-(((7-(cyclopentylamino)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-1-fluorocyclohexyl)methyl)carbamateaccording to the method described for Example 48, step 2. Purificationby prep-HPLC (Agilent 10 prep-C18, 10 m, 250×21.2 mm column, elutingwith a gradient of MeOH in water with 0.1% TFA, at a flow rate of 20mL/min) afforded the title compound. LCMS: [M+H]⁺ 423.1;

¹H NMR (400 MHz, DMSO-d₆) δ 11.6 (br s, 1H), 7.99 (br s, 3H), 6.86 (brs, 1H), 6.42 (dd, J=13.8, 2.1 Hz, 1H), 6.35 (d, J=2.1 Hz, 1H), 3.82-3.74(m, 1H), 3.58 (s, 2H), 3.10-3.00 (m, 2H), 2.77 (m, 1H), 2.05-1.82 (m,6H), 1.75-1.36 (m, 10H).

Further example compounds of the invention prepared by the methodsdescribed herein are provided in Table 10.

TABLE 10 Example Structure/name MS [M + H]⁺ Example 245

394.2 Example 246

391.2 Example 247

392.2 Example 248

391.1 Example 249

406.1 Example 250

471.2 Example 251

364.1 Example 252

388.2 Example 253

394.1 Example 254

441.2 Example 255

433.2 Example 256

404.1 Example 257

373.2 Example 258

423.1 Example 259

455.2 Example 260

321.1 Example 261

377.2 Example 262

399.1 Example 263

459.2 Example 264

437.2 Example 265

363.1 Example 266

413.1 Example 267

467.1 Example 268

494.1 Example 269

485.1 Example 270

426.0 Example 271

378.1 Example 272

407.1 Example 273

481.1 Example 274

419.1 Example 275

346.1 Example 276

483.1 Example 277

422.1 Example 278

364.0 Example 279

463.1 Example 280

378.1 Example 281

468.1 Example 282

392.1 Example 283

448.1 Example 284

395.1 Example 285

416.1 Example 286

433.1 Example 287

423.1 Example 288

475.1 Example 289

377.1 Example 290

392.1 Example 291

365.0 Example 292

364.0 Example 293

392.1 Example 294

396.1 Example 295

382.0 Example 296

426.0 Example 297

382.0 Example 298

504.1 Example 299

486.1 Example 300

472.1 Example 301

464.1 Example 302

449.1 Example 303

395.1 Example 304

427.0 Example 305

396.1 Example 306

367.1 Example 307

436.1 Example 308

407.1 Example 309

377.1 Example 310

394.1 Example 311

420.0 Example 312

472.1 Example 313

410.1 Example 314

407.1 Example 315

401.0 Example 316

444.0 Example 317

415.0 Example 318

423.1 Example 319

409.1 Example 320

395.1

Example 321:(R)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-oneand(S)-5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-2-yl)methoxy)quinazolin-4(3H)-one

Example 320 was further purified by chiral prep-HPLC (Chiralpak IG-3, 3μm, 0.46×5 cm column, eluting with a gradient of (hexane:DCM 1:1)(0.1%diethylamine):EtOH 50:50 at a flow rate of 1.0 mL/min) to afford thetitle compounds with retention times of 2.50 minutes and 3.70 minutes.

Example 321a

LCMS: [M+H]⁺ 395.2; ¹H NMR (400 MHz, DMSO) δ 12.18 (br s, 1H), 6.90-6.87(m, 2H), 4.19-4.16 (m, 2H), 4.15-4.06 (m, 1H), 3.83-3.76 (m, 3H),3.71-3.65 (m, 1H), 3.61 (s, 2H), 3.32-3.29 (m, 2H), 3.08-3.03 (m, 1H),2.01-1.99 (m, 1H), 1.90-1.82 (m, 4H), 1.71-1.67 (m, 1H), 1.49-1.39 (m,2H).

Example 321b

LCMS: [M+H]⁺ 395.2; ¹H NMR (400 MHz, DMSO) δ 12.18 (br s, 1H), 6.91-6.88(m, 2H), 4.17-4.15 (m, 2H), 4.15-4.05 (m, 1H), 3.83-3.78 (m, 3H),3.70-3.65 (m, 1H), 3.62 (s, 2H), 3.33-3.30 (m, 2H), 3.08-3.03 (m, 1H),2.01-1.99 (m, 1H), 1.90-1.82 (m, 4H), 1.72-1.67 (m, 1H), 1.49-1.39 (m,2H).

Example 322:5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one

Step 1: 2-(Chloromethyl)-5,6,7-trifluoroquinazolin-4(3H)-one

Prepared from methyl 6-amino-2,3,4-trifluorobenzoate andchloroacetonitrile according to the method described for Int-A16. LCMS:[M+H]⁺ 249.0.

Step 2:5,6,7-Trifluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from 2-(chloromethyl)-5,6,7-trifluoroquinazolin-4(3H)-one andInt-B1 according to the method described for Example 28. LCMS: [M+H]⁺331.0.

Step 3:5,6,7-Trifluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

To a solution of5,6,7-trifluoro-2-(tetrahydropyran-4-ylsulfanylmethyl)-3H-quinazolin-4-one(52.0 g, 157 mmol) in anhydrous THF (650 mL) at 0° C. under a N₂atmosphere was added KHMDS (1 M solution in THF, 236 mL, 236 mmol) andthe mixture was stirred at 0° C. for 1 h.2-(Chloromethoxy)ethyl-trimethylsilane (41.8 mL, 236 mmol) was thenadded and the mixture was stirred for a further 1.5 h. The reaction wasquenched with water (100 mL) and the mixture was extracted with EtOAc(500 mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (Petroleum ether:EtOAc, 10:1, v/v) to afford the titlecompound (58.0 g, 80%) as a brown oil. ¹H NMR (400 MHz, DMSO-d₆) δ7.59-7.55 (m, 1H), 5.57 (s, 2H), 3.99 (s, 2H), 3.87-3.77 (m, 2H), 3.63(t, J=8.0 Hz, 2H), 3.32-3.29 (m, 2H), 3.15-3.04 (m, 1H), 1.91-1.88 (m,2H), 1.54-1.40 (m, 2H), 0.90 (t, J=8.0 Hz, 2H), 0.04 (s, 9H).

Step 4:5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

To a solution of5,6,7-trifluoro-2-(tetrahydropyran-4-ylsulfanylmethyl)-3-(2-trimethylsilylethoxy-methyl)quinazolin-4-one(1.5 g, 3.3 mmol) in DMSO (15 mL) was added K₂CO₃ (0.99 g, 7.2 mmol) andtetrahydrofuran-3-ylmethanamine (0.40 g, 3.9 mmol) and the mixture washeated at 50° C. overnight. The mixture was diluted with water (20 mL),extracted with EtOAc (30 mL×3) and the combined organic layers werewashed with water (40 mL), dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by preparative TLC (Petroleumether:EtOAc, 3/1, v/v) to afford title compound (560 mg, 32%) as ayellow oil. LCMS: [M+H]⁺ 542.1.

Step 5:5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one

To a solution of5,6-difluoro-7-(tetrahydrofuran-3-ylmethylamino)-2-(tetrahydropyran-4-ylsulfanylmethyl)-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one(560 mg, 1.03 mmol) in DCM (10 mL) was added TFA (5 mL) and the mixturewas stirred at RT for 2 h. The mixture was then concentrated underreduced pressure and the residue was purified by column chromatography(DCM:MeOH, 20/1, v/v) to afford the title compound (220 mg, 50%) as ayellow solid. LCMS: [M+H]⁺ 412.1. ¹H NMR (400 MHz, DMSO-d₆) δ 11.9 (s,1H), 7.00-6.98 (m, 1H), 6.58 (d, J=7.2 Hz, 1H), 3.83-3.68 (m, 4H),3.64-3.61 (m, 1H), 3.59 (s, 2H), 3.50-3.47 (m, 1H), 3.31-3.28 (m, 2H),3.19-3.16 (m, 2H), 3.06-2.99 (m, 1H), 2.59-2.50 (m, 1H), 2.02-1.94 (m,1H), 1.88-1.86 (m, 2H), 1.65-1.57 (m, 1H), 1.48-1.39 (m, 2H).

Example 323:(S)-5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-oneand(R)-5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((tetrahydrofuran-3-yl)methyl)amino)quinazolin-4(3H)-one

Example 322 was further purified by chiral prep-HPLC (Chiralpak IA-3, 3μm, 0.46×5 cm column, eluting with a gradient of (hexane:DCM 3:1)(0.1%diethylamine):EtOH 50:50 at a flow rate of 1.0 mL/min) to afford thetitle compounds with retention times of 2.79 minutes and 4.83 minutes.

Example 323a

LCMS: [M+H]⁺ 412.2; ¹H NMR (400 MHz, DMSO) δ 11.9 (s, 1H), 7.01-7.00 (m,1H), 6.60-6.58 (m, 1H), 3.83-3.69 (m, 4H), 3.65-3.60 (m, 1H), 3.58 (s,2H), 3.51-3.46 (m, 1H), 3.30-3.29 (m, 2H), 3.20-3.17 (m, 2H), 3.07-3.00(m, 1H), 2.59-2.51 (m, 1H), 2.00-1.96 (m, 1H), 1.90-1.86 (m, 2H),1.64-1.63 (m, 1H), 1.49-1.43 (m, 2H).

Example 323b

LCMS: [M+H]⁺ 412.2; ¹H NMR (400 MHz, DMSO) δ 11.9 (s, 1H), 7.01-7.00 (m,1H), 6.60-6.58 (m, 1H), 3.84-3.69 (m, 4H), 3.65-3.59 (m, 1H), 3.58 (s,2H), 3.51-3.47 (m, 1H), 3.32-3.29 (m, 2H), 3.20-3.17 (m, 2H), 3.07-2.99(m, 1H), 2.60-2.51 (m, 1H), 2.00-1.96 (m, 1H), 1.90-1.86 (m, 2H),1.64-1.63 (m, 1H), 1.47-1.42 (m, 2H).

Example 324:5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one

Prepared from Int-A52 and Int-B11 according to the method described forExample 235. LCMS: [M+H]⁺ 409.1; ¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H),6.83 (dd, J=12.6, 2.0 Hz, 1H), 4.13-4.02 (m, 2H), 3.93-3.88 (m, 2H),3.81-3.77 (m, 1H), 3.72-3.66 (m, 1H), 3.65 (s, 2H), 3.55-3.49 (m, 1H),2.80-2.67 (m, 2H), 2.20-2.18 (m, 1H), 2.08-2.04 (m, 2H), 1.96-1.93 (m,2H), 1.78-1.75 (m, 1H), 1.42-1.23 (m, 4H).

Example 325:5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-oneand5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((S)-tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one

Example 324 was further purified by chiral prep-HPLC (Chiralpak IE-3, 3μm, 0.46×5 cm column, eluting with a gradient of MTBE (0.1%diethylamine):MeOH 50:50 at a flow rate of 1.0 mL/min) to afford thetitle compounds with retention times of 2.22 minutes and 3.1 minutes.

Example 325a

LCMS: [M+H]⁺ 409.2; ¹H NMR (400 MHz, CD₃OD) δ 6.93 (s, 1H), 6.82 (dd,J=12.6, 2.0 Hz, 1H), 4.12-4.02 (m, 2H), 3.93-3.88 (m, 2H), 3.81-3.77 (m,1H), 3.72-3.66 (m, 1H), 3.63 (s, 2H), 3.53-3.50 (m, 1H), 2.80-2.71 (m,2H), 2.18-2.09 (m, 1H), 2.08-2.04 (m, 2H), 1.96-1.93 (m, 2H), 1.78-1.77(m, 1H), 1.37-1.26 (m, 4H).

Example 325b

LCMS: [M+H]⁺ 409.2; ¹H NMR (400 MHz, CD₃OD) δ 6 6.93 (s, 1H), 6.82 (dd,J=12.6, 2.0 Hz, 1H), 4.13-4.02 (m, 2H), 3.93-3.88 (m, 2H), 3.81-3.76 (m,1H), 3.72-3.65 (m, 1H), 3.64 (s, 2H), 3.53-3.50 (m, 1H), 2.80-2.70 (m,2H), 2.18-2.08 (m, 1H), 2.07-2.04 (m, 2H), 1.96-1.93 (m, 2H), 1.81-1.77(m, 1H), 1.37-1.26 (m, 4H).

Example 326:5-Fluoro-7-(((trans)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1: trans-tert-Butyl3-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate

The title compound was prepared in two steps from tert-butyl3-fluoro-4-oxo-piperidine-1-carboxylate in 8% overall yield according tothe procedure described in Eur. J. Med. Chem. 2012, 53, 408. ¹H NMR (400MHz, CDCl₃) δ 4.46-4.27 (m, 2H), 4.08-4.02 (m, 1H), 3.80 (dd, J=10.8,4.0 Hz, 1H), 3.70 (dd, J=10.8, 5.2 Hz, 1H), 2.78-2.68 (m, 2H), 1.82-1.78(m, 2H), 1.45 (s, 9H), 1.38-1.32 (m, 1H).

Step 2: tert-Butyl(trans)-3-fluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate

To a solution of trans-tert-butyl3-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (800 mg, 3.43 mmol)and Et₃N (520 mg, 5.14 mmol) in DCM (5 mL) at 0° C. was added MsCl (471mg, 4.12 mmol) and the mixture was stirred at RT for 2 h. Water (20 mL)was added and the mixture was extracted with EtOAc (30 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure to afford the title compound (1.0 g, 94%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 4.44-4.25 (m, 4H), 4.10-4.07 (m, 1H),3.03 (s, 3H), 2.82-2.66 (m, 2H), 2.02-1.95 (m, 1H), 1.88-1.84 (m, 1H),1.52-1.45 (m, 10H).

Step 3:5-Fluoro-7-hydroxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from Int-A53 and Int-B1 according to the method described forExample 202. ¹HNMR (400 MHz, DMSO-d₆) δ 12.0 (s, 1H), 10.9 (s, 1H), 6.70(d, J=2.0 Hz, 1H), 6.66-6.62 (m, 1H), 3.83-3.80 (m, 2H), 3.59 (s, 2H),3.31-3.28 (m, 2H), 3.07-3.00 (m, 1H), 1.90-1.86 (m, 2H), 1.49-1.39 (m,2H).

Step 4: trans-tert-Butyl3-fluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylate

A mixture of tert-butyl(trans)-3-fluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate(800 mg, 2.57 mmol), K₂CO₃ (540 mg, 3.87 mmol) and5-fluoro-7-hydroxy-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one(957 mg, 3.08 mmol) in DMSO (30 mL) was heated at 60° C. overnight. Themixture was allowed to cool to RT, diluted with water (20 mL) andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine (10 mL×3), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by reverse phase column (Biotage, C18column, 0%-60% ACN in water, 0.1% TFA) to afford the title compound (380mg, 28%) as a brown solid. LCMS: [M+H]⁺ 526.2.

Step 5:5-Fluoro-7-(((trans)-3-fluoropiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-oneHydrochloride

To a mixture of trans-tert-butyl3-fluoro-4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylate(380 mg, 0.720 mmol) in EtOAc (5 mL) was added a 2 M solution of HCl inEtOAc (5 mL) and the mixture was stirred at RT for 2 h. The mixture wasconcentrated under reduced pressure to afford the title compound (320mg, 95%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.39 (s, 1H),6.98 (s, 1H), 6.94-6.91 (m, 1H), 4.96-4.84 (m, 1H), 4.28-4.21 (m, 2H),3.84-3.80 (m, 2H), 3.65 (s, 2H), 3.49-3.47 (m, 1H), 3.35-3.30 (m, 2H),3.26-3.18 (m, 1H), 3.17-3.03 (m, 2H), 3.03-2.92 (m, 1H), 2.47-2.35 (m,1H), 2.12-2.02 (m, 1H), 1.91-1.88 (m, 2H), 1.80-1.69 (m, 1H). 1.49-1.39(m, 2H). Two protons not observed (C—NH₂ ⁺—C).

Step 6:5-Fluoro-7-(((trans)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

To a solution of5-fluoro-7-(((trans)-3-fluoropiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-onehydrochloride (320 mg, 0.690 mmol) in methanol (20 mL) was added a 30%aqueous formaldehyde solution (0.2 mL) and NaCNBH₃ (435 mg, 6.93 mmol)and the mixture was stirred at RT for 1 h. Water (5 mL) was then addedand the mixture was extracted with EtOAc (20 mL×3). The combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by column chromatography (DCM:MeOH, 35/1, v/v)to afford the title compound (80 mg, 25%) as a yellow solid. LCMS:[M+H]⁺ 440.1; ¹HNMR (400 MHz, DMSO-d₆) δ 12.2 (s, 1H), 6.91-6.88 (m,2H), 4.64-4.46 (m, 1H), 4.25-4.11 (m, 2H), 3.83-3.80 (m, 2H), 3.62 (s,2H), 3.35-3.34 (m, 1H), 3.29-3.28 (m, 1H), 3.12-3.03 (m, 2H), 2.75-2.67(m, 1H), 2.23 (s, 3H), 2.02-1.87 (m, 6H), 1.55-1.38 (m, 3H).

Example 327:5-Fluoro-7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-oneand5-Fluoro-7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Example 326 was further purified by chiral prep-HPLC (Chiralpak IE-3, 3μm, 0.46×5 cm column, eluting with a gradient of (hexane:DCM 1:1):MeOH50:50 at a flow rate of 1.0 mL/min) to afford the title compounds withretention times of 2.05 minutes and 3.48 minutes.

Example 327a

Chiral prep-HPLC (Chiralpak IE-3, 3 μm, 0.46×5 cm column, eluting with agradient of [hexane:DCM 1:1]:MeOH 50:50 at a flow rate of 1.0 mL/min)retention time: 2.05 minutes; LCMS: [M+H]⁺ 440.2; ¹H NMR (400 MHz, DMSO)δ 12.18 (s, 1H), 6.91-6.88 (m, 2H), 4.68-4.54 (m, 1H), 4.24-4.15 (m,2H), 3.84-3.80 (m, 2H), 3.62 (s, 2H) 3.35-3.34 (m, 1H), 3.29-3.28, (m,1H), 3.11-3.04 (m, 2H), 2.72-2.68 (m, 1H), 2.23 (s, 3H), 2.08-1.83 (m,6H), 1.52-1.41 (m, 3H); [α]_(D)=25.6° (c 0.082 g/100 mL, MeOH).

Example 327b

Chiral prep-HPLC (Chiralpak IE-3, 3 μm, 0.46×5 cm column, eluting with agradient of [hexane:DCM 1:1]:MeOH 50:50 at a flow rate of 1.0 mL/min)retention time: 3.48 minutes; LCMS: [M+H]⁺ 440.2; ¹H NMR (400 MHz, DMSO)δ 12.18 (s, 1H), 6.91-6.88 (m, 2H), 4.62-4.54 (m, 1H), 4.24-4.15 (m,2H), 3.84-3.80 (m, 2H), 3.62 (s, 2H) 3.36-3.35 (m, 1H), 3.32-3.29, (m,1H), 3.11-3.04 (m, 2H), 2.72-2.70 (m, 1H), 2.23 (s, 3H), 2.08-1.83 (m,6H), 1.52-1.41 (m, 3H); [α]D=−27.4° (c 0.084/100 mL, MeOH).

Example 328:5,6-Difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1:5,6-Difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

Prepared from5,6,7-trifluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)-methyl)quinazolin-4(3H)-oneand cis-3-methoxycyclobutanamine hydrochloride according to the methoddescribed for Example 322, step 4. ¹H NMR (400 MHz, DMSO-d₆) δ 7.22 (d,J=6.0 Hz, 1H), 6.49 (d, J=7.2 Hz, 1H), 5.56 (s, 2H), 3.96 (s, 2H),3.90-3.85 (m, 2H), 3.75-3.59 (m, 4H), 3.34-3.20 (m, 2H), 3.19 (s, 3H),3.12-3.08 (m, 1H), 2.78-2.66 (m, 2H), 2.00-1.98 (m, 4H), 1.57-1.45 (m,2H), 0.98-0.84 (m, 2H), 0.00 (s, 9H).

Step 2:5,6-Difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from5,6-difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-oneaccording to the method described for Example 322, step 5. LCMS: [M+H]⁺412.1;

¹H NMR (400 MHz, DMSO-d₆) δ 11.9 (s, 1H), 7.03 (d, J=6.0 Hz, 1H), 6.44(d, J=6.8 Hz, 1H), 3.81-3.79 (m, 2H), 3.68-3.57 (m, 4H), 3.37-3.34 (m,1H), 3.28-3.27 (m, 1H), 3.14 (s, 3H), 3.07-3.00 (m, 1H), 2.77-2.65 (m,2H), 1.95-1.85 (m, 4H), 1.47-1.37 (m, 2H).

Example 329:N-((cis)-4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide

Step 1: tert-Butyl((cis)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)carbamate

Prepared from Int-A49 and Int-B5-cis according to the method describedfor Example 202. LCMS: [M+H]⁺ 478.1.

Step 2:2-((((cis)-4-Aminocyclohexyl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-oneHydrochloride

A mixture of tert-butyl((cis)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)carbamate(150 mg, 0.31 mmol) and a 2 M solution of HCl in EtOAc (10 mL, 20 mmol)was stirred at RT overnight. The solvent was removed under reducedpressure to afford the title compound (80 mg, 67%) as a yellow solid.LCMS: [M+H]⁺ 378.1.

Step 3:N-((cis)-4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide

To a solution of2-((((cis)-4-aminocyclohexyl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-onehydrochloride (80 mg, 0.21 mmol) and Et₃N (96 mg, 0.95 mmol) in DCM (2mL) was added acetic anhydride (48 mg, 0.48 mmol) and the mixture wasstirred at RT for 1 h. Water (5 mL) was added and the mixture wasextracted with EtOAc (20 mL×3). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure to afford the titlecompound (50 mg, 57%) as a white solid. LCMS: [M+H]⁺ 420.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.1 (br s, 1H), 7.75 (d, J=7.6 Hz, 1H),6.90-6.85 (m, 2H), 3.96 (d, J=7.6 Hz, 2H), 3.63-3.57 (m, 1H), 3.56 (s,2H), 3.12-3.05 (m, 1H), 1.77 (s, 3H), 1.71-1.69 (m, 4H), 1.51-1.50 (m,4H), 1.25-1.20 (m, 1H), 0.59-0.56 (m, 2H), 0.35-0.34 (m, 2H).

Example 330:N-((trans)-4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide

Step 1: tert-Butyl((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)carbamate

Prepared from Int-A49 and Int-B5-trans according to the method describedfor Example 202. LCMS: [M+H]⁺ 478.1

Step 2:2-((((trans)-4-Aminocyclohexyl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-oneHydrochloride

Prepared from tert-butyl((trans)-4-(((7-(cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)carbamateaccording to the method described for Example 329, step 2. LCMS: [M+H]⁺378.1.

Step 3:N-((trans)-4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide

Prepared from2-((((trans)-4-aminocyclohexyl)thio)methyl)-7-(cyclopropylmethoxy)-5-fluoroquinazolin-4(3H)-onehydrochloride according to the method described for Example 329, step 3.LCMS: [M+H]⁺ 420.1; ¹H NMR (400 MHz, DMSO-d₆) δ 12.1 (br s, 1H), 7.69(d, J=7.6 Hz, 1H), 6.97-6.73 (m, 2H), 3.95 (d, J=7.2 Hz, 2H), 3.58 (s,2H), 3.53-3.41 (m, 1H), 2.73-2.67 (m, 1H), 2.03-1.93 (m, 2H), 1.79-1.75(m, 2H), 1.75 (s, 3H), 1.34-1.10 (m, 5H), 0.63-0.55 (m, 2H), 0.37-0.32(m, 2H).

Example 331:7-(((cis)-3-Ethoxycyclobutyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1:7-(((cis)-3-Ethoxycyclobutyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one

Prepared from5,6,7-trifluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)-methyl)quinazolin-4(3H)-oneand cis-3-ethoxycyclobutanamine hydrochloride according to the methoddescribed for Example 322 step 4. LCMS: [M+H]⁺ 556.3.

Step 2:7-(((cis)-3-Ethoxycyclobutyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Prepared from7-(((cis)-3-ethoxycyclobutyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-oneaccording to the method described for Example 322 step 5. LCMS: [M+H]⁺426.1.

¹H NMR (400 MHz, DMSO-d₆) δ 11.9 (s, 1H), 7.03 (d, J=6.4 Hz, 1H), 6.44(d, J=6.4 Hz, 1H), 3.84-3.77 (m, 2H), 3.76-3.67 (m, 1H), 3.65-3.55 (m,1H), 3.55 (s, 2H), 3.38-3.29 (m, 4H), 3.05-3.01 (m, 1H), 2.77-2.66 (m,2H), 1.96-1.82 (m, 4H), 1.50-1.38 (m, 2H), 1.10 (t, J=6.8 Hz, 3H).

Example 332:5-Fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one

Prepared from Int-A50 and Int-B16 according to the method described forExample 202. LCMS: [M+H]⁺ 437.1; ¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (br s,1H), 6.89-6.86 (m, 2H), 3.98 (d, J=6.0 Hz, 2H), 3.88-3.85 (m, 2H), 3.55(s, 2H), 3.33-3.30 (m, 2H), 2.98-2.90 (m, 1H), 2.04-1.89 (m, 3H),1.68-1.65 (m, 2H), 1.56-1.48 (m, 2H), 1.42-1.28 (m, 6H), 1.07 (s, 3H).One signal (OH) not observed.

Example 333:7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

Step 1: 1-[4-(Hydroxymethyl)-1-piperidyl]ethanone

The title compound was synthesized from piperidin-4-ylmethanol accordingto the procedure described in U.S. Pat. No. 4,898,871.

Step 2: (1-Acetylpiperidin-4-yl)methyl methanesulfonate

To a solution of 1-[4-(hydroxymethyl)-1-piperidyl]ethanone (3.0 g, 19.1mmol) and Et₃N (3.86 g, 38.2 mmol) in DCM (15 mL) at 0° C. under a N₂atmosphere was added a solution of MsCl (2.22 mL, 28.6 mmol) in DCM (5mL) and the mixture was allowed to warm to RT and stirred for 1 h. Themixture was diluted with DCM (20 mL) and washed with water (10 mL) andbrine (10 mL). The organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure to afford the title compound (4.5 g, 100%) as abrown oil. ¹H NMR (400 MHz, DMSO-d₆) δ 4.43-4.35 (m, 1H), 4.06 (d, J=6.4Hz, 2H), 3.84-3.78 (m, 1H), 3.16 (s, 3H), 3.03-2.96 (m, 1H), 2.53-2.46(m, 1H), 1.98 (s, 3H), 1.95-1.83 (m, 1H), 1.72-1.63 (m, 2H), 1.20-0.99(m, 2H).

Step 3: 2,6-Difluoro-4-hydroxybenzoic acid

The title compound was synthesized from2,6-difluoro-4-hydroxybenzonitrile according to the procedure describedin WO201742380.

Step 4: Methyl 2,6-difluoro-4-hydroxybenzoate

The title compound was synthesized from 2,6-difluoro-4-hydroxybenzoicacid according to the procedure described in WO201123989.

Step 5: Methyl 4-((1-acetylpiperidin-4-yl)methoxy)-2,6-difluorobenzoate

A mixture of (1-acetylpiperidin-4-yl)methyl methanesulfonate (4.55 g,19.4 mmol), methyl 2,6-difluoro-4-hydroxybenzoate (2.6 g, 13.8 mmol) andK₂CO₃ (4.77 g, 34.6 mmol) in DMSO (26 mL) was heated at 80° C. under aN₂ atmosphere overnight. The mixture was diluted with water (100 mL) andextracted with EtOAc (35 mL×3). The combined organic extracts werewashed with water (25 mL), brine (25 mL), dried over Na₂SO₄ andconcentrated under reduced pressure to afford the title compound (4.52g, 100%) as a pale yellow oil. LCMS: [M+H]⁺ 328.1.

Step 6: Methyl4-((1-acetylpiperidin-4-yl)methoxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate

A mixture of methyl4-((1-acetylpiperidin-4-yl)methoxy)-2,6-difluorobenzoate (13.0 g, 39.7mmol), (2,4-dimethoxyphenyl)methanamine (8.95 mL, 59.6 mmol) and K₂CO₃(13.7 g, 99.3 mmol) in NMP (80 mL) was heated at 80° C. for 16 h. Aftercooling to RT, the mixture was diluted with water (200 mL) and extractedwith EtOAc (100 mL×3). The combined organic extracts were dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (Petroleum ether:EtOAc, 3/1, v/v) to afford thetitle compound (15.0 g, 80%) as a yellow solid. LCMS: [M+H]⁺ 475.3.

Step 7: Methyl4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoate

A solution of methyl4-((1-acetylpiperidin-4-yl)methoxy)-2-((2,4-dimethoxybenzyl)amino)-6-fluorobenzoate(12.0 g, 25.3 mmol), triethylsilane (2.94 g, 25.3 mmol) and TFA (50.0mL, 25.3 mmol) in DCM (100 mL) was stirred at 25° C. for 1 h. Themixture was concentrated under reduced pressure and the residue wasdiluted with DCM (50 mL), adjusted to pH 8 with a saturated aqueousNa₂CO₃ solution and extracted with DCM (50 mL×3). The combined organicextracts were dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by column chromatography (DCM:MeOH, 100/1 to50/1, v/v) to afford the title compound (6.2 g, 76%) as a yellow solid.LCMS: [M+H]⁺ 325.2.

Step 8:7-((1-Acetylpiperidin-4-yl)methoxy)-2-(chloromethyl)-5-fluoroquinazolin-4(3H)-one

A mixture of methyl4-((1-acetylpiperidin-4-yl)methoxy)-2-amino-6-fluorobenzoate (20.0 g,55.5 mmol), 2-chloroacetonitrile (10.5 mL, 166 mmol) and a 2 M HCl indioxane solution (90.0 mL, 180 mmol) was heated at 80° C. for 2 h. Themixture was filtered and the collected solid was slurried with water (80mL) for 1 h then filtered. The solid was then slurried with a 60/1DCM/MeOH solution (40 mL) followed by a 100/1 DCM/EtOH solution (60 mL)to afford the title compound (12.0 g, 55%) as a pale yellow solid. LCMS:[M+H]⁺ 368.1.

Step 9:7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one

A mixture of7-((1-acetylpiperidin-4-yl)methoxy)-2-(chloromethyl)-5-fluoroquinazolin-4(3H)-one(10.0 g, 27.2 mmol), 2 M aqueous NaOH (54.4 mL, 109 mmol) and Int-B1(5.23 g, 32.6 mmol) in THF (100 mL) was stirred at RT under a N₂atmosphere for 3 h. The mixture was diluted with water (1 L) andadjusted to pH 1 with a 2 M aqueous HCl solution. The mixture wasstirred for 15 min and then allowed to stand undisturbed for 1 day. Theresulting suspension was filtered and the filter cake was washed withEtOAc (50 mL) and dried to afford the title compound (10.0 g, 82%) as apale yellow solid. LCMS: [M+H]⁺ 450.1;

¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (s, 1H), 6.92-6.96 (m, 2H), 4.40-4.35(m, 1H), 4.00 (d, J=6.4 Hz, 2H), 3.85-3.79 (m, 3H), 3.61 (s, 2H),3.35-3.29 (m, 2H), 3.10-2.97 (m, 2H), 2.57-2.50 (m, 1H), 2.05-1.96 (m,1H), 1.99 (s, 3H), 1.92-1.86 (m, 2H), 1.81-1.73 (m, 2H), 1.49-1.39 (m,2H), 1.30-1.05 (m, 2H).

Example 334:5-Fluoro-7-(((trans)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-oneTrifluoroacetic Acid

Step 1:5-Fluoro-7-hydroxy-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

To a solution of Int-A53 (500 mg, 2.19 mmol) and Int-B11 (434 mg, 3.28mmol) in DMSO (6 mL) under a nitrogen atmosphere was added K₂CO₃ (604mg, 4.37 mmol) and the mixture was stirred at RT overnight. The mixturewas diluted with water (20 mL) and extracted with EtOAc (20 mL×3). Thecombined organic extracts were dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography(DCM:MeOH, 30/1 to 10/1, v/v) to afford the title compound (480 mg, 68%)as a brown solid. LCMS: [M+H]⁺ 325.1.

Step 2: tert-Butyl(trans)-3-fluoro-4-(((5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylate

Prepared from5-fluoro-7-hydroxy-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-oneand tert-butyl (trans)-3-fluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate according to the methoddescribed for Example 326, step 4. LCMS: [M+H]⁺ 540.3.

Step 3:5-Fluoro-7-(((trans)-3-fluoropiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-oneHydrochloride

Prepared from tert-butyl(trans)-3-fluoro-4-(((5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylateaccording to the procedure described for Example 326, step 5. LCMS:[M+H]⁺440.2.

Step 4:5-Fluoro-7-(((trans)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-onetrifluoroacetic acid

Prepared from5-fluoro-7-(((trans)-3-fluoropiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-onehydrochloride according to the procedure described for Example 326, step6. Purification by prep-HPLC (Agilent 10 prep-C18, 10 μm, 250×21.2 mmcolumn, eluting with a gradient of MeOH in water with 0.1% TFA, at aflow rate of 20 mL/min) gave the title compound in 48% yield. LCMS:[M+H]⁺ 454.1;

¹HNMR (400 MHz, DMSO-d₆) δ 12.2 (br s, 1H), 10.2-9.67 (m, 1H), 7.01-6.84(m, 2H), 5.21-4.68 (m, 1H), 4.34-4.21 (m, 2H), 3.83-3.64 (m, 1H), 3.58(s, 2H), 3.50-3.27 (m, 2H), 3.24-2.97 (m, 2H), 2.85-2.81 (m, 3H),2.76-2.67 (m, 1H), 2.59-2.47 (m, 1H), 2.33-2.07 (m, 2H), 2.03-1.63 (m,5H), 1.30-1.10 (m, 4H).

Example 335:5-fluoro-7-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-oneand5-fluoro-7-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one

Example 334 was further purified by chiral prep-HPLC (Chiralpak IE-3, 3μm, 0.46×10 cm column, eluting with a gradient of MeOH:DCM 50:50 at aflow rate of 1.0 mL/min) to afford the title compounds with retentiontimes of 1.85 minutes and 4.13 minutes.

Example 335a

LCMS: [M+H]⁺ 454.2;

¹HNMR (400 MHz, DMSO-d₆) δ 12.15 (s, 1H), 6.91-6.88 (m, 2H), 4.62-4.48(m, 2H), 4.24-4.14 (m, 2H), 3.58 (s, 1H), 3.40-3.33 (m, 1H), 3.11-3.07(m, 1H), 2.75-2.67 (m, 2H), 2.22 (s, 3H), 1.97-1.79 (m, 8H), 1.54-1.45(m, 1H), 1.26-1.11 (m, 5H).

Example 335b

LCMS: [M+H]⁺ 454.2;

¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (s, 1H), 6.91-6.88 (m, 2H), 4.62-4.52(m, 2H), 4.24-4.15 (m, 2H), 3.58 (s, 1H), 3.39-3.35 (m, 1H), 3.11-3.07(m, 1H), 2.75-2.67 (m, 2H), 2.23 (s, 3H), 1.98-1.79 (m, 8H), 1.54-1.45(m, 1H), 1.28-1.11 (m, 5H).

Further example compounds of the invention prepared by the methodsdescribed herein are provided in Table 11.

TABLE 11 Example Structure/Name MS [M + H]⁺ Example 336

424.1 2-((((trans)-4-(Aminomethyl)-4-fluorocyclohexyl)thio)methyl)-7-(cyclobutylmethoxy)-5-fluoroquinazolin-4(3H)-one Example 337

382.0 7-((Cyclopropylmethyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 338

426.1 5,6-Difluoro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 339

444.0 7-((Cyclobutylmethyl)amino)-2-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)thio)methyl)-5,6-difluoroquinazolin-4(3H)-one Example 340

410.1 (racemic)5-Fluoro-7-(((trans)-2-fluorocyclopentyl)amino)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one Example 341

410.1 (racemic)5-Fluoro-7-(((cis)-2-fluorocyclopentyl)amino)-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one Example 342

423.0 5-Fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one Example 343

381.1 5-Fluoro-7-(oxetan-3-ylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 344

411.0 (racemic)7-((1,4-Dioxan-2-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 345

428.1 (racemic)7-((2,2-Difluorocyclohexyl)amino)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 346

508.1 5,6-Difluoro-7-(((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 347

508.1 5,6-Difluoro-7-(((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 348

412.0 (R)-5,6-Difluoro-7-((tetrahydro-2H-pyran-3-yl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 349

453.0 7-(((R)-1-Acetylpyrrolidin-3-yl)amino)-5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)- one Example350

428.0 (racemic)7-((2,2-Difluorocyclopentyl)amino)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one Example 351

457.0 7-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin- 4(3H)-oneExample 352

426.0 (racemic) 5-Fluoro-7-(((trans)-3-fluoropiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 353

425.0 5-Chloro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 354

521.0 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-((1-(3,3,3-trifluoropropyl)piperidin-4-yl)amino)quinazolin- 4(3H)-oneExample 355

437.1 (racemic)7-((5,5-Dimethyltetrahydrofuran-3-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)- one Example356

437.1 5-Fluoro-2-((((trans)-4-methoxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one Example 357

437.1 5-Fluoro-2-((((cis)-4-methoxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one Example 358

423.1 5-Fluoro-2-(((4-methyltetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one Example 359

409.1 (racemic) 5-Fluoro-7-(((cis)-2-hydroxycyclopentyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 360

435.1 (trans)-4-((5,6-Difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)cyclohexane-1-carbonitrile Example 361

435.1 (cis)-4-((5,6-Difluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)amino)cyclohexane-1-carbonitrile Example 362

412.0 5,6-Difluoro-7-(((trans)-3-methoxycyclobutyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 363

426.0 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((cis)-3-methoxycyclobutyl)amino)quinazolin-4(3H)-one Example 364

405.0 5-Methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 365

423.1 5-Fluoro-2-((((cis)-4-hydroxycyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one Example 366

443.0 2-(((4,4-Difluorocyclohexyl)thio)methyl)-5-fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one Example 367

436.1 (racemic)7-((1-Acetylpyrrolidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 368

405.1 7-(2-Cyclohexylethyl)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 369

467.1 7-(((1-Acetylpiperidin-4-yl)methyl)amino)-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 370

425.0 5-Fluoro-7-(((tetrahydro-2H-pyran-4-yl)methyl)thio)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 371

412.1 (racemic) 5-Fluoro-7-(((cis)-4-fluoropyrrolidin-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 372

426.1 5-Fluoro-7-(((cis)-4-fluoro-1-methylpyrrolidin-3-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)- one Example373

423.1 (racemic) 5-Fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one Example 374

440.1 5,6-Difluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-(((cis)-3-methoxycyclobutyl)amino)quinazolin-4(3H)-one Example 375

491.0 5-Fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-((((trans)-4-(trifluoromethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)- one Example376

455.0 (racemic) 5-Bromo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)quinazolin-4(3H)-one Example 377

454.1 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((trans)-4-methoxycyclohexyl)amino)quinazolin-4(3H)-one Example 378

434.1 N-((trans)-4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)propionamide Example 379

454.1 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((cis)-4-methoxycyclohexyl)amino)quinazolin-4(3H)-one Example 380

434.1 N-(4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)-1- methylcyclohexyl)acetamideExample 381

426.1 5,6-Difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)-7-(((R)-tetrahydro-2H-pyran-3-yl)amino)quinazolin-4(3H)-one Example 382

395.1 5-Fluoro-2-((((trans)-3-hydroxycyclobutyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one Example 383

402.1 (racemic) 4-Oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-((tetrahydrofuran-3-yl)methoxy)-3,4-dihydroquinazoline-5- carbonitrileExample 384

398.1 5,6-Difluoro-7-(neopentylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 385

409.1 5-Fluoro-7-(((cis)-3-hydroxy-3-methylcyclobutyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 386

409.1 5-Fluoro-7-(((trans)-3-hydroxy-3-methylcyclobutyl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)- one Example387

436.1 N-((cis)-3-(((5-Fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2- yl)methyl)thio)cyclobutyl)acetamideExample 388

440.1 (racemic)5-Fluoro-7-(((cis)-3-fluoro-1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)- one Example389

467.1 N-((trans)-4-(((5,6-Difluoro-7-(((cis)-3-methoxycyclobutyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide Example 390

476.1 7-((1-(Cyclopropanecarbonyl)piperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin- 4(3H)-oneExample 391

450.1 (racemic) N-((trans)-4-(((5-Fluoro-4-oxo-7-((tetrahydrofuran-3-yl)methoxy)-3,4-dihydroquinazolin-2- yl)methyl)thio)cyclohexyl)acetamideExample 392

437.1 N-((trans)-4-(((7-(Cyclobutylamino)-5,6-difluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)thio)cyclohexyl)acetamide Example 393

436.1 N-((trans)-3-(((5-Fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2- yl)methyl)thio)cyclobutyl)acetamideExample 394

407.1 (racemic)7-(1-Cyclopentylethoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one Example 395

446.1 N-((trans)-4-(((7-(Cyclopropylmethoxy)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)methyl)thio)cyclohexyl)cyclopropanecarboxamideExample 396

464.1 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one Example 397

478.1 5-Fluoro-7-((1-isobutyrylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 398

464.1 5-Fluoro-7-((1-propionylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 399

408.1 5-Fluoro-7-(piperidin-4-ylmethoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 400

440.1 (racemic)5,6-Difluoro-7-((1-(tetrahydro-2H-pyran-4-yl)ethyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 401

450.1 (racemic)7-((1-Acetylpiperidin-3-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 402

466.0 5,6-Difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(((cis)-3-(trifluoromethoxy)cyclobutyl)amino)quinazolin- 4(3H)-oneExample 403

328.0 7-Amino-5,6-difluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 404

406.1 7-(Cyclopropylmethoxy)-2-((((trans)-4-(dimethylamino)cyclohexyl)thio)methyl)-5-fluoro-7,8-dihydroquinazolin-4(3H)-one Example 405

395.1 5-Fluoro-2-((((cis)-3-hydroxycyclobutyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one Example 406

427.0 5,6-Difluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 407

414.1 5,6-Difluoro-7-((2-methoxy-2-methylpropyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 408

457.1 (racemic) 5,6-Difluoro-7-((((cis)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 409

478.1 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((cis)-4-hydroxy-4-methylcyclohexyl)thio)methyl)quinazolin-4(3H)- one Example 410

466.0 Methyl 4-(((5-fluoro-4-oxo-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-3,4-dihydroquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylate Example 411

437.1 5-Fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)thio)methyl)-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4(3H)-one Example 412

409.2 (racemic) 7-(Cyclopentylamino)-5-fluoro-2-((((trans)-3-fluoro-1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one Example 413

409.0 (racemic) 7-(Cyclopentylamino)-5-fluoro-2-((((cis)-3-fluoro-1-methylpiperidin-4-yl)thio)methyl)quinazolin-4(3H)-one Example 414

424.0 (racemic) 5-Fluoro-7-((4-methylmorpholin-2-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 415

422.1 5-Fluoro-7-((1-methylpiperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 416

381.1 5-Fluoro-7-(neopentyloxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 417

478.1 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((trans)-4-hydroxy-4-methylcyclohexyl)thio)methyl)quinazolin-4(3H)- one Example 418

491.1 5-Fluoro-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2-((((cis)-4-(trifluoromethoxy)cyclohexyl)thio)methyl)quinazolin-4(3H)- one Example419

481.0 7-(((1-Acetylpiperidin-4-yl)methyl)amino)-5,6-difluoro-2-((((trans)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)- one Example420

341.9 5,6-Difluoro-7-(methylamino)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 421

435.0 5-Fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)-7-(3,3,3-trifluoro-2,2-dimethylpropoxy)quinazolin-4(3H)-one Example 422

464.1 7-((1-Acetylpiperidin-4-yl)methoxy)-5-fluoro-2-((((cis)-4-hydroxycyclohexyl)thio)methyl)quinazolin-4(3H)-one Example 423

466.0 7-((1-Acetylpiperidin-4-yl)methoxy)-5-chloro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 424

480.0 5-Fluoro-7-((1-(2-methoxyacetyl)piperidin-4-yl)methoxy)-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one Example 425

457.0 (racemic) 5,6-Difluoro-7-((((trans)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-2-(((tetrahydro-2H-pyran-4-y1)thio)methyl)quinazolin-4(3H)-one Example 426

464.1 N-((trans)-4-(((5-Fluoro-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-3,4-dihydroquinazolin-2- yl)methyl)thio)cyclohexyl)acetamideExample 427

458.0 (Racemic)

Example A. Enzymatic Assay for Inhibition of PARP14

The catalytic domain of human PARP14 (residues 1611 to 1801, GenBankAccession No. NM_017554) was overexpressed in Escherichia coli cells. AnN-terminal His-TEV fusion tag was used to purify the protein from celllysates. The His-TEV tag was left on the protein for use in theenzymatic assay.

Enzymatic inhibition of PARP14 was measured using adissociation-enhanced lanthanide fluorescence immunoassay (DELFIA)monitoring the auto-modification of PARP14 by biotinylated nicotinamideadenine dinucleotide (biotin-NAD). 1 μL of a dose response curve of eachtest compound was spotted in 384-well nickel-coated white microplates(Thermo) using a Mosquito (TTP Labtech). Reactions were performed in a50 μL volume by adding 40 μL of PARP14 in assay buffer (20 mM HEPESpH==8, 100 mM NaCl, 0.1% bovine serum albumin, 2 mM DTT and 0.002%0Tween20), incubating with test compound at 25° C. for 30 min, thenadding 10 μL of biotin-NAD (Biolog). The final concentrations of PARP14and biotin-NAD are 50 nM and 3 μM, respectively. Reactions proceeded at25° C. for 3 h, then were quenched with 5 μL of 10 mM unmodifiednicotinamide adenine dinucleotide (Sigma-Aldrich). The quenchedreactions were washed 3 times with 100 μL of TBST wash buffer (50 mMTris-HCl, 150 mM NaCl and 0.1% Tween20). Next, to the washed and driedplate was added 25 μL of DELFIA Europium-N1 streptavidin (Perkin Elmer)diluted in DELFIA assay buffer (Perkin Elmer) After a 30 min incubationat 25° C., the plate was washed 5 times with TBST wash buffer. Finally,25 μL of DELFIA enhancement solution was added. After a 5 min incubationthe plate was read on an Envision platereader equipped with aLANCE/DELFIA top mirror (Perkin Elmer) using excitation of 340 nm andemission of 615 nm to measure the amount of Europium present in eachwell, informing on the amount of biotin-NAD that was transferred in theautomodification reaction. Control wells containing a negative controlof 20% DMSO vehicle or a positive control of 100 μM rucaparib were usedto calculate the 0% inhibition as described below:

${\%\mspace{14mu}{inhibition}} = {100 \times \frac{{{ex}\; 615_{cmpd}} - {{ex}\; 615_{m\; i\; n}}}{{{ex}\; 615_{m\;{ax}}} - {{ex}\; 615_{m\; i\; n}}}}$where ex615_(cmpd) is the emission from the compound treated well,ex615_(min) is the emission from the rucaparib treated positive controlwell and ex615_(max) is the emission from the DMSO treated negativecontrol well.

The % inhibition values were plotted as a function of compoundconcentration and the following 4-parameter fit was applied to derivethe IC₅₀ values:

$Y = {{Bottom} + \frac{\left( {{Top} - {Bottom}} \right)}{\left( {1 + \left( \frac{X}{{IC}_{50}} \right)^{{Hill}\mspace{14mu}{Coefficient}}} \right.}}$where top and bottom are normally allowed to float, but may be fixed at100 or 0 respectively in a 3-parameter fit. The Hill Coefficient isnormally allowed to float but may also be fixed at 1 in a 3-parameterfit. Y is the % inhibition and X is the compound concentration.

IC₅₀ data for the Example compounds is provided below in Table A-1 (“+”is <1 μM; “++” is ≥1 μM<10 μM; and “+++” is ≥10 μM).

TABLE A-1 Example IC₅₀ PARP14 No. (μM) 1 +++ 2 + 3 ++ 4 +++ 5 ++ 6 ++ 7+++ 8 + 9 ++ 10 +++ 11 +++ 12 ++ 13 + 14 ++ 15 ++ 16 ++ 17 ++ 18 + 19+++ 20 + 21 + 22 + 23 + 24 ++ 25 +++ 26 ++ 27 ++ 28 +++ 29 ++ 30 ++ 31++ 32 ++ 33 + 34 + 35 + 36 +++ 37 +++ 38 +++ 39 +++ 40 +++ 41 +++ 42 +++43 +++ 44 + 45 ++ 46 ++ 47 ++ 48 ++ 49 ++ 50 ++ 51 + 52 ++ 53 + 54 ++ 55++ 56 + 57 + 58 + 59 + 60 + 61 + 62 + 63 ++ 64 + 65 ++ 66 + 67 + 68 ++69 + 70 ++ 71 ++ 72 +++ 73 + 74 +++ 75 +++ 76 ++ 77 +++ 78 +++ 79 + 80 +81 ++ 82 ++ 83 ++ 84 ++ 85 ++ 86 ++ 87 ++ 88 +++ 89 ++ 90 ++ 91 ++ 92 ++93 +++ 94 + 95 ++ 96 ++ 97 ++ 98 + 99 ++ 100 + 101 + 102 + 103 + 104 ++105 + 106 ++ 107 + 108 + 109 ++ 110 ++ 111 ++ 112 ++ 113 +++ 114 ++115 + 116 + 117 ++ 118 ++ 119 + 120 +++ 121 + 122 + 123 + 124 + 125 ++126 ++ 127 +++ 128 ++ 129 ++ 130 ++ 131 ++ 132 +++ 133 +++ 134 ++ 135+++ 136 + 137 + 138 + 139 + 140 + 141 ++ 142 + 143 ++ 144 ++ 145 + 146 +147 + 148 + 149 ++ 150 ++ 151 + 152 + 153 + 154 + 155 + 156 ++ 157 + 158++ 159 ++ 160 ++ 161 ++ 162 + 163 ++ 164 ++ 165 + 166 + 167 ++ 168 ++169 + 170 + 171 + 172 + 173 ++ 174 + 175 ++ 176 + 177 + 178 ++ 179 +180 + 181 + 182 ++ 183 ++ 184 + 185 + 186 + 187 + 188 +++ 189 ++ 190 +191 ++ 192 + 193 + 194 + 195 + 196 + 197 + 198 ++ 199 + 200 + 201 + 202++ 203 + 204 ++ 205 + 206 + 207 +++ 208 + 209 + 210 + 211a + 211b +212 + 213a + 213b + 214 + 215 + 216 ++ 217 + 218 + 219 + 220 + 221 ++222 + 223 + 224 ++ 225 +++ 226 + 227 ++ 228 ++ 229 + 230 ++ 231 + 232 +233 + 234 ++ 235 + 236 + 237 + 238 + 239a + 239b + 240 + 241 + 242 ++243 + 244 + 245 ++ 246 + 247 + 248 + 249 + 250 + 251 + 252 + 253 + 254 +255 + 256 + 257 + 258 + 259 + 260 +++ 261 + 262 + 263 + 264 + 265 +266 + 267 + 268 + 269 + 270 + 271 + 272 ++ 273 + 274 + 275 + 276 + 277 +278 + 279 + 280 + 281 + 282 + 283 + 284 + 285 + 286 + 287 + 288 + 289 ++290 + 291 + 292 + 293 + 294 + 295 + 296 + 297 ++ 298 + 299 + 300 + 301 +302 + 303 + 304 + 305 + 306 ++ 307 + 308 + 309 + 310 + 311 ++ 312 +313 + 314 + 315 + 316 + 317 + 318 + 319 + 320 + 321a + 321b + 322 +323a + 323b + 324 + 325a + 325b + 326 + 327a + 327b + 328 + 329 + 330 +331 + 332 + 333 + 334 + 335a + 335b + 336 ++ 337 + 338 + 339 + 340 +341 + 342 + 343 + 344 + 345 + 346 + 347 + 348 + 349 + 350 + 351 + 352 ++353 + 354 + 355 + 356 + 357 + 358 + 359 + 360 + 361 + 362 + 363 + 364 +365 + 366 + 367 + 368 ++ 369 + 370 + 371 + 372 + 373 + 374 + 375 + 376 +377 + 378 + 379 + 380 + 381 + 382 + 383 + 384 + 385 + 386 + 387 + 388 +389 + 390 + 391 + 392 + 393 + 394 + 395 + 396 + 397 + 398 + 399 + 400+++ 401 + 402 + 403 +++ 404 + 405 + 406 + 407 ++ 408 ++ 409 + 410 +411 + 412 + 413 + 414 + 415 + 416 + 417 + 418 + 419 + 420 + 421 + 422 +423 + 424 + 425 + 426 + 427 +

Example B: mRNA Expression Levels of PARP14 in Various Cancer Types

FIG. 1 illustrates the mRNA expression levels of PARP14 in variouscancer types, compared to their matched normal tissue. RNA sequencingdata were downloaded from The Cancer Genome Consortium (TCGA) andanalyzed. Individual dots represent values from individual samples,boxes represent the interquartile or middle 50% of the data withhorizontal lines being the group median, vertical lines representing theupper and lower quartiles of the data. It is apparent that PARP14 mRNAis higher, compared to normal tissue, in several cancer types.BLCA=bladder cancer, BRCA=breast cancer, ESCA=esophageal cancer,HNSC=head and neck cancer, KIRP=papillary kidney cancer, KIRC=clear cellkidney cancer, READ=rectal cancer, STAD=stomach cancer, THCA=thyroidcancer, UCEC—uterine cancer. * p<0.05, ** p<0.01, *** p<0.001, Wilcoxontest.

Example C: Reduction of IL-10 Production in Cells by Treatment withPARP14 Inhibitors

FIGS. 2A and 2B illustrate that in vitro treatment with various PARP14inhibitors decreases IL-10 production in IL-4 stimulated M2-likemacrophages. Figure A) Experimental layout. Monocytes were isolated fromperipheral human blood and cultured in the presence of M-CSF and PARP14inhibitors (at 10 or 3 μM) for 96 h. M-CSF differentiates monocytes intoM-0 macrophages. Subsequently medium was replaced with fresh mediumcontaining IL-4 and PARP14 inhibitors (at 10 or 3 μM), and cells wereincubated for another 48 h. Figure B) IL-10 levels in tissue culturesupernatant, measured by ELISA, of cells treated as described under A. *p<0.5, ** p<0.01, *** p<0.001; statistical significance was determinedby the Holm-Sidak method.

Isolation of primary human monocytes from whole blood: Primary monocyteswere isolated from whole blood (iSPECIMEN; 500 mL) collected fromhealthy donors. Blood was diluted at a 1:1 ratio with EasySep buffer(STEMCELL Technologies 20144) and layered onto lymphoprep (STEMCELLTechnologies 07811) in SepMate tubes (STEMCELL Technologies 85450) forPBMC isolation according to the manufacturer's instructions. Theisolated PBMCs were pooled, washed with EasySep buffer, resuspended inthe appropriate volume of ammonium chloride solution (STEMCELLTechnologies 07850; 10-15 mL) for RBC lysis, and gently shaken for 10minutes. The total volume was increased to 40 mL with EasySep buffer todilute the RBC lysis, then cells were centrifuged at 1500 rpm for 5minutes. Fresh EasySep buffer was used to resuspend PBMCs for counting.The EasySep human monocyte isolation kit (STEMCELL Technologies 19359)was used to isolate monocytes from the PBMC cell population according tothe manufacturer's instructions. The enriched monocyte cell populationwas resuspended in fresh EasySep buffer for counting and seeding forsubsequent assays.

Monocyte to macrophage differentiation, M2 polarization, and PARP14inhibition: Monocytes were seeded on day 0 in ImmunoCult SF macrophagemedium (STEMCELL Technologies 10961) containing 50 ng/mL M-CSF (STEMCELLTechnologies 78057) at a density of 1 million cells per 1 mL of media in12-well plates and allowed to grow and differentiate into macrophagesfor 6 days. On day 4, one half of the initial volume of media was addedto each well. Six days after monocyte seeding, cells were treated with 3ng/mL human recombinant IL-4 (STEMCELL Technologies 78045) and sampleswere collected (media and cells) at 24, 48, and 72 hours. Cells weretreated with PARP14 inhibitors (Examples 102, 108, and 115) or DMSO onday 2 or day 4 after seeding at 10 μmol/L and 3 μmol/L.

IL-10 determination: Levels of IL-10 in the supernatants of humanprimary M2 macrophages were determined with the IL-10 ELISA kit(STEMCELL Technologies 02013) according to the manufacturer'sinstructions. Briefly, supernatants were collected at the indicated timepoints and depleted of any floating cells before being stored at −80° C.until ready to use. Supernatants were diluted at a ratio of 1:3 for theassay and concentrations were determined from the kit's IL-10 standardcurve and normalized to total cell protein.

Example D: Inhibition of Tumor Growth by Treatment with a PARP14Inhibitor

FIGS. 3A and 4A illustrate that a PARP14 inhibitor (Example 235) reducestumor growth in the murine syngeneic models (A) 4T1 and (B) LL/2. Forthe 4T1 study (FIGS. 3A and 3B), female BALB/c mice were inoculatedorthotopically in the mammary fat pad with 1×10⁵ 4T1 cells (ATCC,CRL-2539™) for tumor development. Seven days after tumor inoculation, 16mice with tumor size ranging from 41-78 mm³ (average tumor size 56 mm³)were selected and assigned into 2 groups using stratified randomizationwith 8 mice in each group based upon their tumor volumes. The treatmentswere started from the next day post randomization (defined asrandomization day DO) and were treated with vehicle (0.5%methylcellulose+0.2% Tween 80), or the compound of Example 235 (500mg/kg PO BID*21 days). The tumor sizes were measured three times perweek during the treatment. The entire study was terminated on D20. Tumorgrowth inhibition of 31% was observed for the treatment group versus thevehicle group.

For the LL/2 study (FIGS. 4A-4C), female C57BL/6 mice were inoculatedsubcutaneously in the right flank with 5×10{circumflex over ( )}5 LL/2cells (ATCC, CRL-1642™) for tumor development. Five days after tumorinoculation, 16 mice with tumor size ranging from 37-72 mm³ (averagetumor size 51 mm³) were selected and assigned into 2 groups usingstratified randomization with 8 mice in each group based upon theirtumor volumes. The treatments were started from the next day postrandomization (defined as randomization day DO) and were treated withvehicle (0.5% methylcellulose+0.2% Tween 80), or the compound of Example235 (500 mg/kg PO BID*21 days). The tumor sizes were measured threetimes per week during the treatment. The entire study was terminated onD21. Tumor growth inhibition of 63% was observed for the treatment groupversus the vehicle group.

Mean tumor volume and SEM for both studies were plotted and are shown inFIGS. 3A and 4A. Statistical significance, calculated using 2 way ANOVAmultiple comparisons in which each treatment group was compared tovehicle control, is indicated by an asterisk. Statistics were performedon groups with less than 20% animal loss (D20 for 4T1, D17 for LL/2).Survival benefit was determined for the LL/2 study (FIG. 4B). Individualmice were euthanized once they reached the termination endpoint (TV>2000mm3). The time from treatment initiation to termination was deemed asits survival time and plotted in a Kaplan-Meier survival curve format.Mice remaining at study end date of 21 days were euthanized at day 21after treatment initiation. The plasma concentration of the compound ofExample 235 at 2 and 12 hours following the last dose at study endpointis plotted (FIGS. 3B and 4C).

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A method of treating cancer in a patient in needof treatment comprising administering to said patient a therapeuticallyeffective amount of a compound, which is7-((1-acetylpiperidin-4-yl)methoxy)-5-fluoro-2-(((tetrahydro-2H-pyran-4-yl)thio)methyl)quinazolin-4(3H)-one,or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1wherein said cancer is multiple myeloma, DLBCL, hepatocellularcarcinoma, bladder cancer, esophageal cancer, head and neck cancer,kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroidcancer, uterine cancer, breast cancer, glioma, follicular lymphoma,pancreatic cancer, lung cancer, colon cancer, or melanoma.